PREPARATION OF TETRAHYDROINDAZOLE DERIVATIVES AS NOVEL DIACYLGLYCERIDE O-ACYLTRANSFERASE 2 INHIBITORS

PREPARATION DE DERIVES DE TETRAHYDROINDAZOLE EN TANT QUE NOUVEAUX INHIBITEURS DE DIACYLGLYCERIDE O-ACYLTRANSFERASE 2

English Abstract

Invented are compounds of formula I and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are DGAT2 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases and heart failure and related diseases and conditions, comprising administering a compound of Formula I to a patient in need thereof.

French Abstract

L'invention concerne des composés de formule I et des sels, esters et promédicaments pharmaceutiquement acceptables associés, qui sont des inhibiteurs de diaglycéride O-acyltransférase 2 (DGAT2). L'invention concerne également des procédés de fabrication de composés de formule I, des compositions pharmaceutiques comprenant des composés de formule I et des procédés d'utilisation de ces composés pour traiter la stéatose hépatique, la stéatohépatite non alcoolique (SHNA), la fibrose, le diabète sucré de type 2, l'obésité, l'hyperlipidémie, l'hypercholestérolémie, l'athérosclérose, le déclin cognitif, la démence, les maladies cardiorénales telles que les maladies rénales chroniques et l'insuffisance cardiaque et des maladies et affections associées, comprenant l'administration d'un composé de formule I à un patient en ayant besoin.

Claims

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WHAT IS CLAIMED IS:
1. A compound of Formula I:
R1
R4 y"X
R3
0 R2
or pharmaceutically acceptable salts thereof wherein:
X and Y are independently selected from 0 or C(R5)2; wherein X and Y are both
not 0; and
le is
(1) phenyl unsubstituted or substituted with 1, 2, or 3 R6,
(2) 5- or 6-membered heteroaryl containing 1, 2, 3 or 4
heteroatoms independently
selected from N, 0, and S, wherein the heteroaryl is unsubstituted or
substituted
with 1, 2, or 3 R6, or
(3) 8- to 10- membered fused heteroaryl containing 1, 2, 3
heteroatoms
independently selected from N, 0, and S, wherein the heteroaryl is
unsubstituted
or substituted with 1, 2, or 3 R6;
R2 is
(1) aryl unsubstituted or substituted with 1, 2, or 3 R7,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, 0, and S, wherein the heteroaryl is unsubstituted or
substituted
with 1, 2, or 3 R7.
(3) C1-6alkyl unsubstituted or optionally mono-substituted, disubstituted
or
trisubstituted with halogen, OH, CF3, -CN, or (C3-6)cycloalkyl,
(4) (C3-6)cycloalkyl unsubstituted or optionally mono-
substituted, disubstituted or
trisubstituted with C1-6alkyl, halogen, OH, CF3, or -CN,
(5) -(C3-6)alkylC(0)NH2,
(6) 4- to 6- membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S wherein the heterocyclyl is unsubstituted or
substituted
by 1, 2, or 3 R7,
(7) -CH2-aryl unsubstituted or substituted by 1, 2, or 3
R7,
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(8) -CH2-heterocycly1 unsubstituted or substituted by 1, 2, or 3 R7,
(9) -C(=0) (C1-6)a1ky1 unsubstituted or substituted with 1, 2, or 3 R7,
(10) -C(=0) (C3-6)cycloalkyl unsubstituted or substituted with 1, 2, or 3 R7,
(11) -C(=0) (C1-6)heterocycly1 unsubstituted or substituted with 1, 2, or 3
R7,
(12) -C(=0) aryl unsubstituted or substituted with 1, 2, or 3 R7,
(13) -S02(C1-6)alkyl unsubstituted or substituted with 1, 2, or 3 R7, or
(14) -S02-aryl unsubstituted or substituted with 1, 2, or 3 117;
R3 is
(1) 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, a and S,
(3) -(C1-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered
heteroaryl
containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S,
(4) -(CI-6)alkyl-aryl,
(5) -(C1-6)alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S,
(6) -(C1_6)alkyl,
(7) -(C3_6)cycloalkyl,
(8) -(C3-6)cycloalkyl-heterocycly1 wherein the heterocyclyl is a 3-to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S,
(9) -(C1-6)hydroxyalkyl,
(10) -(C1-6)alkyl-S(0)2-NR8aR8b,
(11) -(C1-6)alkyl-S(0)2-(C1-3)alkyl,
(12) -(C1_3)alkyl-heteroaryl, wherein the heteroaryl is an 8- to 10- membered
fused
ring, and wherein the heteroaryl contains 1, 2, 3, or 4 heteroatoms
independently
selected from N, 0, and S,
(13) -(C1-6)alkyl-SONH-(C1-3)alkyl,
(14) -(C1-6)alkyl-(C3-6)cycloalkyl,
(15) fused aryl,
(16) -C(1-6)alkyl-N(R11)2,
(17) -C(1-6)alkyl-O-C1-3alkyl, or
(18) -C(1-6)alkyl-O-C3-6cycloalkyl,
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wherein each aryl, fused aryl, heteroaryl, cycloalkyl, or heterocyclyl is
unsubstituted or
substituted with 1, 2, or 3 R9, and wherein each alkyl is unsubstituted or
substituted with 1, 2, or
3 Rio;
R4 is
(1) hydrogen,
(2) (C1_3)alkyl,
or R5 and R4, together with the nitrogen atom to which they are attached,
combine to form a
mono- or bicyclic heterocyclyl ring containing 1 N and optionally containing 1
additional
heteroatoms independently selected from N, 0 and S, wherein the heterocyclyl
ring is
unsubstituted or substituted by 1, 2, or 3 R' ';
when present, each R5 is selected from
(1) hydrogen,
(2) halogen, or
(3) cyano;
when present, each R6 is independently selected from
(1) cyano,
(2) halogen,
(3) (C1-6)alkyl or 0C1-6alkyl wherein the alkyl moiety is optionally
substituted with
cyano,
(4) (C3-6)cycloalkyl, optionally substituted with halogen, C1-6alkyl, C1-
6haloalkyl,
cyano, OH or 0C1-6alkyl,
(5) -C(0)N(R11)2,
(6) (C3-6)cycloalkyloxy wherein the cycloalkyl is optionally substituted
with halogen,
C1-6alkyl, C1-6haloalkyl, cyano, OH, or 0C1-6alkyl,
(7) hydroxy,
(8) _NRiiRii;
(9) (C1-6)haloalkyl-,
(10) (C1-6)haloalkoxy-,
(11) -S02(C1-6)alkyl,
(12) -SONH(C1-6)alkyl,
(13) C1-6alkyl-NRIIRli; or
(14) 5 membered heteroaryl comprising 2 nitrogen atoms;
when present, each R7is independently selected from
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(1) (C1_6)alkyl,
(2) halo,
(3) (C1-6)alkoxy-,
(4) (C1-6)haloalkyl-,
(5) (C3-6)cycloalkyl,
(6) C(0)H or -C(0)-0H,
(7) C(0)(C1-6)alkyl or -C(0)0-(C1-6)alkyl,
(8) hydroxy,
(9) CN,
(10) deuterium,
(11) 0C1-3haloalkyl, or
(12) oxo;
when present, R8a and R" are independently selected from
(1) hydrogen,
(2) (C1_3)alkyl,
(3) -(C1-3)alkyl-phenyl,
(4) 5- or 6-membered heteroaryl containing 1, 2, or 3
heteroatoms independently
selected from N, 0, and S, or
(5) phenyl;
when present, each R9 is independently selected from
(1) (C1-3)alkyl,
(2) (C1-3)haloalkyl-,
(3) oxo,
(4) (C3-6)cycloalkyl,
(5) -C(0)0-(C1-4)alkyl,
(6) -NR11R11,
(7) hydroxy,
(8) phenyl, unsubstituted or substituted with halo,
(9) hydroxy(C1-3)alkyl-,
(10) cyano,
(11) halo,
(12) C(0)C1-6alkyl or C(0)C3-6cycloalkyl,
(13) C(0)NHC1-3alkyl, or
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(14) 6 membered heterocycle containing one Oxygen and one Nitrogen;
when present, R' is
(1) (C1-3)alkyl,
(2) (C1-3) hydroxy alkyl-,
(3) (C1-3)alkoxy-,
(4) hydroxy,
(5) halogen,
(6) (C1-3)haloalkyl-,
(7) N(RH)2,
(8) (C1-3)a1ky1-S-, or
(9) phenyl;
when present, RH is independently
(1) hydrogen, or
(2) (C1_6)alkyl;
when present, Ru, Rua and R'211 are independently
(1) hydrogen,
(2) (C1-6)alkyl,
(3) (C3-6)cycloalkyl, or
(4) (C1_6)haloalkyl.
2. The compound of claim 1, or a pharmaceutically acceptable
salt thereof, wherein RI-
is
(a) phenyl substituted with one to three substituents independently selected
from hydroxy,
halogen, hydroxy, CN, C1-3alkyl, C1-3alkyl-CN, 0C1-3alkyl-CN , C1-3haloalkyl,
C3-
6cycloalkyl, -0C1-3alkyl, -0C1-3haloalkyl, -0C3-6cycloalkyl, 5 membered
heteroaryl
containing 2 nitrogen atoms, S(0)2C1-6alkyl, S(0)2NHC1-3alkyl, or C1-
3a1ky1NH2. and
optionally further substituted with 1 or 2 substituents independently selected
from
halogen, C1-3alkyl, C1-3haloalkyl, CN, or OH;
(b) a 6 membered heteroaryl containing one or two nitrogen atoms substituted
with one to
two substituent selected from: halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, C3-
6cycloalkyl,
-0C1-3haloalkyl, -0-C3_6cycloalkyl, C(0)NC1-6alkyl, or CN, and optionally
further substituted with 1 or 2 fluoro atoms or C1-3a1ky1;
(c) a 5 membered heteroaryl containing one to four nitrogen atoms or
heteroatoms
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independently selected from N, 0, and S optionally substituted with one to two

substituents independently selected from with halogen, (C1-3)a1ky1, (C3-
6)cycloalkyl, (Ci-
3)haloalkyl-, OH or 0C1-3alkyl; or
(d) 8- to 10- membered fused heteroaryl containing at least one nitrogen and
optionally
containing one oxygen optionally substituted with 1 or 2 substituents
independently
selected from halogen, C1-3alkyl, C1-3haloalkyl, 0C1-3alkyl, or 0C1-
3haloalkyl.
3. The compound of any of claims 1-2, or a
pharmaceutically acceptable salt
thereof, wherein Rl is
(a) phenyl substituted with a substituent selected from: hydroxy. halogen. CN,
C1-3alkyl, CI-
3alkyl-CN, 0C1-3alkyl-CN, C1-3haloalkyl, C3-6cycloalkyl, -0C1-3alkyl, -0C1-
3haloalkyl, -
0-cyclopropyl, 5 membered heteroaryl containing 2 nitrogen atoms, S(0)2C1-
3alkyl,
S(0)2NHC1-3alkyl, or C1-3a1ky1NH2, and optionally further substituted with 1
or 2
substituents independently selected from F, CH3, CF3, CN, or OH;
(b) a 6 membered heteroaryl containing one or two nitrogen atoms substituted
with one or
two substituents selected from: halogen, hydroxy, C1-3alkyl, C1-3haloalkyl, -
0C1-3alkyl, -
0C1-3haloalkyl, -0-cyclopropyl, or C(0)NHC1-6alkyl, and optionally further
substituted
with 1 or 2 fluorine atoms or CH3;
(c) 5 membered heteroaryl containing one to four nitrogen atoms or heteroatoms
independently selected from N, 0, and S optionally substituted with one to two
substituents independently selected from with halogen, (C1-3)alkyl; or
(d) 9 or 10- membered fused heteroaryl containing one or two heteroatoms
independently
selected from nitrogen or oxygen optionally substituted with 1 or 2 methyl
substituents.
4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt
thereof,
wherein Rl is
F
giOF F * F
F
CI
\3, * s,õ *
F o=
F F F
0
\
\kF F
F F CI F
F F
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D F 0
_N_N.)--3(-k-D * \K-F F * 5...... F 4* 4 CI ...... Ni.....F
D D
D Fi 'F F
F
F IP' CN
F Nr * F3C ()\--- *
ci i\---p¨ )c-F 2.9"- >i¨ * F
F
F F F F
F
2
'
2
HO CN 0
= F < N-
=
orCN
Ni7).
*
#ift 'N
-' *
/ 0 "
* * F NC F F
F .0
NH2 b H
F
--N 9.-0
F
F * N.--- * c7. , )---F
F
, , or .
5. The compound of any of claims 1-4, or a phamiaceutically acceptable salt
thereof,
N
/ 0
* (j),..-F r\ij.. )...-F F * N.i......F F = ....... Nr"F
F2.--1.' (j\......CF3
F F F F
wherein R' is ,
or
iNro
F 1 ....-
6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt
thereof,
wherein R' is
(a) phenyl unsubstituted or substituted with 1, 2, or 3 R7,
(b) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, O. and S, wherein the heteroaryl is unsubstituted or
substituted
with 1, 2, or 3 R7,
(c) C1-6alkyl unsubstituted or mono-substituted, di substituted, or
trisubstituted with
halogen, OH, CF3, -CN, deuterium, or (C3-6)cycloalkyl,
(d) (C3-6)cycloalkyl unsubstituted or optionally mono-substituted,
disubstituted or
trisubstituted with Ci_6a1ky1, halogen, OH, CF3, or -CN,
(e) -(C3-6)alkylC(0)NH2,
(0 4- to 6- membered heterocyclyl containing 1 or 2
heteroatoms independently
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selected from N, 0 and S wherein the heterocyclyl is unsubstituted or
substituted
by 1, 2, or 3 R7,
(g) -CH2-heteroaryl unsubstituted or substituted by 1, 2, or 3 R7,
(h) -CH2-aryl unsubstituted or substituted by 1, 2, or 3 R7,
(i) -CH2-heterocycly1 unsubstituted or substituted by 1, 2, or 3 R7,
(j) -C(=0) (Ci-6)alkyl unsubstituted or substituted with 1, 2, or 3 R7,
(k) -C(=0) (C3-6)cycloalkyl unsubstituted or substituted with 1, 2, or 3
R7,
(1) -C(=0) (C1-6)heterocycly1 unsubstituted or substituted
with 1, 2, or 3 R7,
(m) -C(=0) aryl unsubstituted or substituted with 1, 2, or
3 R7,
(n) -S02(C1-6)alkyl unsubstituted or substituted with 1, 2, or 3 R7,
(o) -S02(C3-6)cyc1oa1ky1 unsubstituted or substituted with 1, 2, or 3 R7,
or
(p) -S02-aryl unsubstituted or substituted with 1. 2, or 3 R7.
7. The compound of any of claims 1-6, or a
pharmaceutically acceptable salt thereof,
wherein R2 is
(a) phenyl unsubstituted or substituted with 1, 2, or 3 R7,
(b) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently
selected
from N and S, wherein the heteroaryl is unsubstituted or substituted with 1 or
2
halogen, Ch3alkyl, or cyclopropyl,
(c) C1-6alkyl unsubstituted or mono-substituted, disubstituted, or
trisubstituted with
halogen, OH, CF3, -CN, deuterium, or (C3-6)cycloalkyl,
(d) (C3-6)cycloalkyl unsubstituted or optionally mono-substituted,
disubstituted or
trisubstituted with halogen, C1-6alkyl, 0C1-3haloalkyl, OH, CF3, or -CN,
(e) -(C3-6)alkylC(0)NH2,
(f) 4- to 6- membered heterocyclyl containing 1 or 2 heteroatoms independently
selected
from N, 0 and S wherein the heterocyclyl is unsubstituted or substituted with
1 or 2
substituents selected from CH3 or oxo,
(g) -CH2-heteroaryl unsubstituted or substituted with 1 or 2 methyl
substituents,
(h) -CH2-aryl,
(i) CH2-heterocyclyl,
(j) -C(=0) (C1_6)alkyl,
(k) -C(=0) (C3-6)cycloalkyl,
(1) -C(-0) (C1-6)heterocyclyl,
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(m) -C(=0) aryl,
(n) -S 02(C 1-6)a1kyl,
(o) -S02(C3-6)cycloalkyl, or
8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt
thereof,
wherein R2 is
(a) phenyl unsubstituted or substituted with halogen or OCHF2,
(b) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently
selected
from N and S, wherein the heteroaryl is unsubstituted or substituted with 1 or
2
halogen, C1-3alkyl, or cyclopropyl,
(c) Ci-6alkyl unsubstituted or mono-substituted, disubstituted, or
trisubstituted with
halogen, OH, CF3, -CN, deuterium, or (C3-6)cycloalkyl,
(d) (C3-6)cycloalkyl unsubstituted or optionally mono-substituted,
disubstituted or
trisubstituted with halogen, Ci-6alkyl, 0C1-3haloalkyl, OH, CF3, or -CN,
1 5 (e) -(C3-6)alkylC(0)NH2,
(1) 4- to 6- membered heterocyclyl containing 1 or 2 heteroatoms independently
selected
from N, 0 and S wherein the heterocyclyl is unsubstituted or substituted with
1 or 2
substituents selected from CH3 or oxo,
(g) -CH2-heteroaryl unsubstituted or substituted with 1 or 2 methyl
substituents,
(h) -CH2-aryl,
(i) -CH2-heterocyclyl,
(j) -C(=0) (C 1-6)alkyl,
(k) -C(=0) (C3-6)cycloalkyl,
(1) -C(=0) (C1-6)heterocyclyl,
(m) -C(=0) aryl,
(n) -S02(C1-6)alkyl, or
(o) -S02(C3-6)cycloalkyl.
9. The compound of anv of claims 1-8, or a
pharmaceutically acceptable salt thereof,
wherein R2 is
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411 F N j'T=N
Nq Nq
NTIJN,c7 j..T.) .0Z
F F 1110
D;PD T."1/ FF
d 0 D
D D
H
70 H %OH c:r0 H 'RE:r0H :1 .1Z
01-1%
OH 0 0
IP
, or
10. The compound of any of claims 1-9, or a
pharmaceutically acceptable salt thereof,
wherein 12' is
(a) 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms independently
selected
from N, 0 and S,
(b) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently
selected
from N, 0, and S,
(c) -(C1-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered
heteroaryl
containing 1, 2, or 3 heteroatoms independently selected from N, 0 and S,
(d) -(C1-6)alkyl-aryl,
(e) -(C1-6)alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered
ring containing
1 or 2 heteroatoms independently selected from N, 0 and S,
(f) -(C1-6)alkyl,
(g) -(C3-6)cycloalkyl,
(h) -(C3-6)cycloalkyl-heterocycly1 wherein the heterocyclyl is a 3-to 6-
mernbered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S.
(i) -(C1-6)hydroxyalkyl,
(j) -(C1 -6) alkyl-S(0)2-NR8aR8b,
(k) -(C1_6)alkyl-S(0)2-(C1_3)alkyl,
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(1) -(C1-3)alkyl-heteroaryl, wherein the heteroaryl is an 8- to 10- membered
fused ring, and
wherein the heteroaryl contains 1, 2, 3, or 4 heteroatoms independently
selected from N,
0, and S,
(m)-(C1-6)alkyl-SONH-(C1-3)alkyl,
(n) -(C1-6)alkyl-(C3-6)cycloalkyl,
(o) fused aryl,
(p) -C(1-6)alkyl-N(R11)2,
(q) -C(1-6)alkyl-O-C1-3alkyl, or
(r) -C(1-6)alkyl-O-C3-6cycloalkyl,
wherein each aryl, fused aryl, heteroaryl, cycloalkyl, or heterocyclyl is
unsubstituted or
substituted with 1, 2, or 3 R9, and wherein each alkyl is unsubstituted or
substituted with 1, 2, or
3 Rio.
11. The compound of any of claims 1-10, or a
pharmaceutically acceptable salt
thereof, wherein -12.' is
(a) 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms
independently selected
from N, 0 and S,
(b) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently selected
from N, 0, and S,
(c) -(C1-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered
heteroaryl
containing 1, 2, or 3 heteroatoms independently selected from N, 0 and S,
(d) -(C1-6)alkyl-aryl,
(e) -(C1-6)alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-
membered ring containing
1 or 2 heteroatoms independently selected from N, 0 and S,
(f) -(C1_6)alkyl,
(g) -(C3-6)cycloalkyl,
(h) -(C3-6)cycloalkyl-heterocycly1 wherein the heterocyclyl is a 3-to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S, or
(1) -(C1-6)alkyl-S(0)2-NR8aR8b,
(j) -C(1-6)alkyl-O-C1-3alkyl, or
(k) -C(1-6)alkyl-O-C3-6cycloalkyl,
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wherein each aryl, fused aryl, heteroaryl, cycloalkyl, or heterocyclyl is
unsubstituted or
substituted with 1, 2, or 3 R9, and wherein each alkyl is unsubstituted or
substituted with 1, 2, or
3 Rm.
12. The compound of
any of claims 1-11, or a pharmaceutically acceptable salt
thereof, wherein R3 is
N
(S1)11 Ho
AA 13.A r-A
fe'S Os r..- 0=-7S 098,,, OdA Od)14- F o .S
'll F-71.3A
o-11 ... 1.,
,
HO\
(-3
F
F_e
FF)Lox\
, ce...... 0 ..01,,4,. 6),.,
1 0, ,.....A
.?,,\__N\___."----s.:'=
".. .
F N N Et0 N \---.
(=,... ,,,),õ
c:4---µ ig
INI.N..Z.IN
,i. r-----N----T\
(..,x),.. 0, ,3,...AN¨ )..._µ s HCrYll .eXµita Y
,
OzzaN
Ozss.......) ..,.N..s.......,....\
0* .0
1 0 0 , 0 , or .
13. The compound of any of claims 1-12, or a pharmaceutically acceptable
salt
thereof, wherein re is H.
14. The compound of any of claims 1-12, or a pharmaceutically acceptable
salt
thereof, wherein R5is H, halogen, or CN.
15. The compound of any of claims 1-14, or a pharmaceutically acceptable
salt
thereof, wherein R5is H, F. Cl, or CN.
16. The compound of any of claims 1-15, or a pharmaceutically acceptable
salt
thereof, wherein R6is halogen, hydroxy, CN, C1-3alkyl, C1-3haloalkyl, C3-
6cycloalkyl, OC1-3alkyl,
OC1-3haloalkyl, 0C3-6cycloalkyl, S(0)2C1-3alkyl, S(0)2NHC1-3alkyl, C(0)NHC1-
3alkyl, Ci-
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6a1ky1NRHRH, or 5 membered heteroaryl with 2 N atoms, and wherein the
cycloalkyl is
optionally substituted with halogen.
17. The compound of any of claims 1-16, or a pharmaceutically acceptable
salt
thereof, wherein R6is Ci-3alkyl, 0-C3-6cycloalkyl, 0C1-3alkyl, S(0)2C1-3alkyl,
S(0)2NHC1-3alkyl,
C(0)NHC1-3alkyl, C1-6a1ky1NR"R", or 5 membered heteroaryl with 2 N atoms, and
wherein the
cycloalkyl is additionally optionally substituted with 1-3 F.
18. The compound of any of claims 1-17, or a pharmaceutically acceptable
salt
thereof, wherein R6 is CH3, OCH2CH3, C(0)NHC(CH3)3, C(CH3)2NH2, S(02)CH3,
S(02)NHCH2CH3, OCD2CD3, pyrazolidine, or 0-cyclopropyl, and wherein the
cyclopropyl is
additionally optionally substituted with one to three halogen atoms. CN, CF3,
or OH.
19. The compound of any of claims 1-18, or a pharmaceutically acceptable
salt
thereof, wherein R7is halogen, oxo, C1-6alkyl, OCI-6haloalkyl, CN, deuterium,
or C3-6cycloalkyl.
20. The compound of any of claims 1-19, or a pharmaceutically acceptable
salt
thereof, wherein R7is F, Cl, oxo, OCHF2, CH3, CN, deuterium, or cyclopropyl.
21. The compound of any of claims 1-20, or a pharmaceutically acceptable
salt
thereof, wherein R8a and leb are independently selected from hydrogen or (C1-
3)alkyl.
22. The compound of any of claims 1-21, or a pharmaceutically acceptable
salt
thereof, wherein R9 is =0, halogen, OH, C1-6alkyl, C1-6haloalky, C1-3alkyl-CN,
C(0)C3-
6cycloalkyl, C(0)C1-3a1ky1OH, C(0)NHC1-3alkyl, or C1-6a1ky1OH, or a 6 membered
heterocycle
containing one Oxygen and one Nitrogen atom.
23. The compound of any of claims 1-21, or a pharmaceutically acceptable
salt
thereof, wherein R9 is =0, CH3, CH2CH3, F, CF3, CH3CN, C(0)cyclopropyl,
C(0)EtO,
CH(CH3)2, or C(0)NHCH(CH3)2, or a 6 membered heterocycle containing one Oxygen
and one
Nitrogen atom.
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24. The compound of any of claims 1-23, or a pharmaceutically acceptable
salt
thereof, wherein Rm is =0, halogen, OH, Ci-6alkyl, C1-6ha1oa1ky, or C1-
6a1ky1OH.
25. The compound of any of claims 1-24, or a pharmaceutically acceptable
salt
thereof, wherein RIR is OH, CH3, or OCH3.
26. The compound of any of claims 1-25, or a pharmaceutically acceptable
salt
thereof, wherein X and Y are C(R5).
27. The compound of any of claims 1-25, or a pharmaceutically acceptable
salt
thereof, wherein X is 0, and Y is C(R5)
28. The compound of any of claims 1-25, or a pharmaceutically acceptable
salt
thereof, wherein X is C(R5), and Y is O.
29. The compound of any of claims 1-28, or a pharmaceutically acceptable
salt
thereof, which is
3-(2-chloropheny1)-1-(4-fluoropheny1)-N-(0-3-methyl-1,1-
dioxidotetrahydrothiophen-3-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(5)-3-(2-chloropheny1)-1-(4-fluoropheny1)-N-((5)-3-methyl-1,1-
dioxidotetrahydrothiophen-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(2-chloropheny1)-1-(4-fluoropheny1)-N-((5)-3-methyl-1,1-
dioxidotetrahydrothiophen-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(4-fluoropheny1)-N-(0-3-methyl-1,1-
dioxidotetrahydrothiophen-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-((S)-3-methy1-1,1-

dioxidotetrahydrothiophen-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-(3-methy1-1,1-
dioxidothietan-3-y1)-4,5,6,7-tetrahydro-111-indazole-6-carboxamide,
1-(5-cyclopropy1-1,3,4-thiadiazol-2-y1)-3-(5-(difluoromethoxy)pyridin-3-y1)-N-
((S)-3-
methyl-1,1-dioxidotetrahydrothiophen-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide,
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(R)-3 -(3 -(di fluo romethoxy)pheny1)-1 -(5-fluoropy ri din-2-y1)-N-((R)-3-
methyltetrahy drofuran-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carboxami de,

(R)-3 -(3 -(di fluo romethoxy)pheny1)-1 -(5-fluoropy ri din-2-y1)-N-(0)-3-
methyltetrahy drofuran-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-N -(3 ,3 -difluor o -1 -methyl cy cl obuty1)-3 -(3 -
(difluoromethoxy)pheny1)-1 -(5 -
fluoropy ri din-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-N-((R)-3,3-difluo ro-1 -(hy droxymethyl)cy cl op enty1)-3 -(3 -(difl
uoromethoxy)pheny1)-
1-(5 -fl uoropy ri din-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami d
e,
(R)-N-((S)-3,3-difluoro -1 -(hy droxymethyl)cy clop enty1)-3 -(3 -
(difluoromethoxy)pheny1)-
1-(5-fl uoropy ri din-2-y1)-4,5, 6,74 etrahy dro-1H-indazole-6-carboxamide,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -(3,5-difluoropy ri din-2-y1)-N-(3-
methy1-1,1-
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxami de,
1-(5-chl oropyrimi di n-2-y1)-3-(3 -(di fl uorometh oxy)pheny1)-N-(0)-3 -
methyl -1,1-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
((R)-3-(5-(difluoromethoxy)-2-fl uoroph eny1)-1-(3,5 -di fl uoropyri din-2-y1)-
N-(3 -methyl -
1,1-di oxi dothietan-3 -y1)-4,5,6,7-tetrahy dro-1H-indazole-6-carb oxami de,
(R)-3 -(5 -(difluo romethoxy)pyri din-3-y1)-1-(5-fluoropyri din-2-y1)-N-(3 -
methy 1-1,1-
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxami de,
(R)-3 -(3 -(3,3-difluoro cy cl obutyl)pheny1)-1-(4-fluoropheny1)-N-(0)-3 -
methyl-1,1-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(5 -(di fluo romethoxy)py ri din-3-y1)-1-(5-fluoropyri din-2-y1)-N-((S)-
3 -methyl-1,1-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-N-((S)-3-cy anotetrahydrofuran-3-y1)-3-(5-(difluoromethoxy )py ri din-3-
y1)-1-(5-
fluoropy ri din-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-N -((R)-3 -cy anotetrahy drofuran-3-y1)-3-(5-(difluoromethoxy)pyri din-3-
y1)-1-(5-
fluoropy ri din-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
3-(3 -(difluoromethoxy)pheny1)-1-(5 -fluoropyri din-2-y1)-N-((1R,2R)-2-
morpholino cy cl openty1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3-(2-( difluoromethoxy )-5-fluoropyridin-4-y1)-1-isopropyl-/V-(4-methyl-
1,1-
di oxi dotetrahy dro-2H-thi opy ran-4-y1)-4,5,6,7-tetrahy dro-1H-in dazol e-6-
carb oxami de,
(R)-3 -(2-ethoxy -5 -fluoropyri din-4-y1)-1-is opro pyl-N-(4-methy1-1,1-di oxi
dotetrahy dro-
2H-thi opy ran-4-y1)-4,5 ,6,7-tetrahy dro-1H-ind azol e-6-carboxami de,
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(R)-3 -(3 -(difluoromethoxy)pheny1)-N-(3 -methyl-1,1-dt oxi dothi etan-3 -y1)-
1 -(tetrahy dro-
2H-py ran-4-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carboxami de,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1-(1,1-di oxi dotetrahy dro-2H-thi opy
ran-4-y1)-N-((S)-
3-methy1-1,1-di oxi dotetrahy drothiophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol
e-6-
carboxamide,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1-is opropyl-N-((5)-3 -methyl-1,1-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -is opropyl-N-(3-methy1-1,1 -di oxi
dothi etan-3-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(3 -(difl uoromethoxy )pheny1)-1 -(tetrahy dro-2H-pyran-4-y1)-N-(2-(6-
(trifluoromethy Opy ri din-3-yl)propan-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-
6-
carb oxamide,
(R)-3 -(5 -(di fl uo rometh oxy)-2-fl uoroph eny1)-1-i s opropyl -N-((S)-3 -m
ethyl -1,1-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(5 -(di fl uo rometh oxy)-2-fl uoroph eny1)-1-i s opropyl -N - ((R)-3 -
m ethyl -1,1-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-111-indazol e-6-
carboxami de,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-1-is opropyl-N-(4-methy1-1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-in dazol e-6-
carb oxami de,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -is opropyl-N-(4-methy1-1,1 -di oxi d
otetrahydro-2H-
thi opy ran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-3 -(3 -cy cl oprop oxypheny1)-1-is opropyl-N-(4-methy1-1,1 -di oxi
dotetrahy dro-2H-
thi opy ran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-3 -(3 -ethoxy pheny1)-1-is o pro pyl-N-(4-methy1-1,1 -di oxi dotetrahy dro-
2H-thi o py ran-4-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(2-ethoxy -5 -fluoropyri din-4-y1)-1-is opro pyl-N-(3-methy1-1,1-di oxi
dothi etan-3-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)- 1 s opropyl-N-(0)-3 -methy1-1,1-di oxi dotetrahy drothi ophen-3-y1)-3-(3 -
(2,2,2-
trifluoroethoxy)pheny1)-4,5,6,7-tetrahy dro-1H-indazole-6-carb oxamide,
(R)- 1 -is opropy1-1V-(4-methyl-1,1-th oxi dotetrahy dro-2H-tht opy ran-4-y1)-
3-(3 -(1,1,2,2-
tetrafluoroethoxy)pheny1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(2-cy cl oprop oxy -5 -fluoropyri din-4-y1)-1-is opropyl-N-(4-methy1-
1,1 -
di oxi d otetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-in d azol e-6-
carb oxami de,
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(R)-3 -(5 -fluoro-2-isopropoxy py ri din-4-y1)-1-is opropyl-N-(4-methy1-1,1-
di oxi d otetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-in d azol e-6-
carb oxami de,
(R)-3 -(5 -chloro-2-ethoxypy ri din-4-y1)-1 -is op ropyl-N-(4-methy1-1,1 -di
oxi dotetrahy dro-
2H-thi opy ran-4-y1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-3-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-y1)-1-is opropyl-N-(4-methy 1-
1,1-
di oxi d otetrahy dro-2H-thi opyran-4-y 0-4,5,6,7-tetrahy dro-1H-in d azol e-6-
carb oxami de,
(R)-3 -(2-(difluo romethoxy)-5-fluoropyri din-4-y1)-1-is opropyl-N-(0)-3 -
methy 1-1,1-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(5 -(difluo romethoxy)-2-(difluoromethyl)pyri din-3-y1)-1-is op ropyl-N-
(4-methyl-
1,1-di oxi dotetrahy dro-2H-thiopyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazole-6-
carboxamide,
(R)-3 -(5 -fluoro-2-(2,2,2-trifluoroethoxy)py ri din-4-y1)-1-i s opropyl-N-(3-
methy1-1,1-
di oxi dothi etan-3-y1)-4,5,6,7-tetrahydro-1H-indazol e-6-carboxami de,
(R)-3 -(5 -fluoro-2-(2,2,2-trifluoroethoxy)py ri din-4-y1)-1 s opropyl-N-((S)-
3 -methyl-1,1 -
di oxi dotetrahydrothi oph en-3 -y1)-4,5,6,7-tetrahy dro-1H-in dazol e-6-
carboxami de,
(R)-3 -(5 -fluoro-2-(2,2,2-trifluoroethoxy)py ri din-4-y1)-1 s opropyl-N-(4-
methy1-1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-in dazol e-6-
carb oxami de,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-N-(4-methy1-1,1-di oxidotetrahy
dro-2H-
thi opy ran-4-y1)-1-(prop an-2-yl-d7)-4,5,6,7-tetrahy dro-1H-indazole-6-
carboxamide,
(R)-3 -(2-ethoxy -5 -fluoropy ri din-4-y1)-N-(4-methy1-1,1-di oxi dotetrahy
dro-2H-thi opyran-
4-y1)-1-(propan-2-yl-d7)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-1 -((R)-1,1-difluoropropan-2-y1)-
N-(3-
methy1-1,1-dioxidothielan-3-y1)-4,5,6,7-tetrahy dro-1H-indazole-6-carboxamide,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-1 -((5)-1,1-difluoropropan-2-y1)-
N-(3 -
methy1-1,1-di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-1 - (( R) - 1,1-difluoroprop an-
2-y1)-N-(4-
methyl-1,1 -di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-
indazol e-6-
carb oxamide,
(R)-3-(5-(difluoromethoxy )-2-fluoropheny1)-14(S)-1,1-difluoropropan-2-y1)-N-
(4-
methyl-1,1 -di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-
indazol e-6-
carb oxamide,
(R)-3 -(2-(ethoxy-c/5)-5 -fluoropy ri din-4-y1)-1 s opropyl-N-(4-methy1-1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-in dazol e-6-
carb oxami de,
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(R)-N-(4-cy ano-1,1 -di oxi dotetrahy dro-2H-thi opy ran-4-y1)-3-(5 -(difluo
romethoxy)-2-
fluoropheny1)-1 -(propan-2-yl-d7)-4,5,6,7-tetrahy dro-1H-ind azol e-6-
carboxami d e,
(R)-N-(4-cy ano-1,1 -di oxi dotetrahy dro-2H-thi opy ran-4-y1)-3-(5 -(difluo
romethoxy)-2-
fluoropheny1)-1 s opropy1-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(2-ethoxy -5 -fluoropy ri din-4-y1)-N-(4-methy1-1,1 -di oxi dotetrahy
dro-2H-thi opyran-
4-y1)-1 -((R)-1,1,1-trifluoropropan-2-y1)-4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide,
(R)-3 -(2-ethoxy -5 -fluoropy ri din-4-y1)-N-(4-methy1-1,1 -di oxi dotetrahy
dro-2H-thi opyran-
4-y1)-1-((S)-1,1,1-trifluoroprop an-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(5 -ethoxy -2-fluoropheny1)-1-i s opropyl-N-(4-methy1-1,1-di oxi
dotetrahy dro-2H-
thi opy ran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)- 1 - s opropyl-N-(4-methy1-1,1-di oxi dotetrahy dro-2H-thi opy ran-4-y1)-3-
(3 -
(tri fluoromethoxy)ph eny1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(5 -(di fl uo rom eth oxy)pyri di n-3-y1)-1-i s opropyl-N-(4-methy1-1,1-
di oxi dotetrahy dro-
2H-thi opy ran-4-y1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-1-cycl obutyl -3-(5-(di fl uorom eth oxy)-2-fl uoroph eny1)-N-(3-methyl -
1,1 -
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxami de,
(R)- 1 - ((R)- 1-cy cl opropylethyl)-3-(5-(difluoromethoxy )-2-fluoropheny1)-N-
(3 -methyl-1,1 -
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxami de,
(R)-1-(0)-1-cy cl opropyl ethyl)-3-(5-(difluoromethoxy)-2-fluoropheny1)-N-(3 -
methyl-1,1-
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxami de,
ethyl 3-((R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-14 s op ropy1-4,5,6,7-
tetrahy dro-1H-
indazol e-6-carb oxami do)-3-methy 1pyrroli dine-1 -carb oxyl ate,
(6R)-3 -(5-(difluoromethoxy)-2-fluoro pheny1)-1-i s o pro py 1-N-(1 -(i s o
pro pyl carbamoy1)-3 -
methylpyrroli din-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(6 R) -N - ( 1-(cy cl oprop anecarb ony1)-3-methylpyrroli din-3 -y1)-3 -(5 -
(difluorometh oxy)-2-
fluoropheny1)-1 s opropy1-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(2-fluoro-5-i sopropoxy pheny1)-1 s opropyl-N-(3-methy1-1,1-di oxi
dothi etan-3-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(5 -( ch fluo romethoxy )-2-fluoropheny1)-1-is opropyl-N-(3-methyl-1,1-
dioxi dothi etan-
3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(5 -cy cl opropy1-2-fl uoropheny1)-1-i s opropyl-N-(3 -methyl-1 ,1 -di
oxi dothietan-3-y1)-
4,5,6,7-tetrahydro-1H-indazole-6- carboxami de,
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(R)-3 -(2-chloro-5 -(difluoromethoxy)pheny1)-1 -is opropyl-N-(3 -methyl-1,1-
di oxi d othi etan-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxami d e,
(R)-3 -(5 -cy cl oprop oxy-2-fluoropheny1)-1-is opropyl-N-(3 -methyl-1,1 oxi
dothietan-3-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(5 -(difluo romethoxy)-2-methylpyri din-3 -y1)-1 -is opropyl-N-(3 -
methyl-1,1-
di oxi d othi etan-3-y 0-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxami d e,
(R)-3 -(5 -ethoxy -2,3-difluoropheny1)-1-is opropyl-N-(3-methy1-1,1-di oxi
dothi etan-3-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(2-chl oro-5 -(trifluoromethoxy)py ri din-3 -y1)-1-is opropyl-N-(3-
methy1-1,1 -
dioxidothietan-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-N -(3 ,3 -difluoro-1 -methyl cy cl obuty1)-3 -(5 -(difluoromethoxy)-2-
methylpyri din-3 -y1)-
1-is opropy1-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-1 -isopropyl -N-(3-methy1-1,1-di oxi dothi etan-3-y1)-3-(5-(1,1,2,2-
tetrafluoroethoxy)pyri din-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-c arb
oxami de,
(R)- 1 -isopropyl -N-((S)-3-methy1-1,1-di oxi dotetrahydrothi oph en-3-y1)-3-
(5 -(1,1,2,2-
tetrafluoroethoxy)pyri din-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-c arb
oxami de,
(R)- 1 -is opropyl-N-(4-methyl-1,1-di oxi dotetrahy dro-2H-thi opy ran-4-y1)-3-
(5 -(1,1,2,2-
tetrafluoroethoxy)pyri din-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-c arb
oxami de,
(R)-3 -(5 -fluoro-2-(2,2,2-trifluoroethoxy)py ri din-4-y1)-1-((R)-3 -hy droxy-
3-methy1butan-
2-y1)-N-(4-methy1-1,1 -di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-
tetrahy dro-1H-
indazole-6-carboxami de,
(R)-3 -(5 -fluoro-2-(2,2,2-trifluoroethoxy)py ri din-4-y1)-1-((S)-3-hy droxy -
3-methylbutan-2-
y1)-N-(4-methy1-1,1-di oxi do tetrahy dro-2H-thiopyran-4-y1)-4,5,6,7-
tetrahydro-1H-
indazole-6-carboxamide,
(R)-3 -(2-ethoxy -5 -fluoropyri din-4-y1)-1-((R)-3 -hy droxy-3 -methy1butan-2-
y1)-N-((S)-3 -
methyl-1,1 -di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol
e-6-
carb oxamide,
(R)-3 -(2-ethoxy -5 -fluoropyri din-4-y1)-1-(0-3 -hy droxy-3-methy lbutan-2-
y1)-N-(0-3-
methyl-1,1-dt oxi dotetrahy drothi ophen-3-y1)-4,5,6, 7-tetrahy dro-111-
indazol e-6-
carboxamide,
(R)-3 -(2-ethoxy -5 -fluoropyri din-4-y1)-1-((R)-3 -hy droxy-3 -methy1butan-2-
y1)-N-(4-
methyl-1,1 -di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5, 6,7-tetrahy dro-1H-
indazol e-6-
carb oxamide,
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(R)-3 -(2-ethoxy -5 -fluoropyri din-4-y1)-1-((S)-3 -hy droxy-3-methy lbutan-2-
y1)-N-(4-
methyl-1,1 -di oxi d otetrahy dro-2H-thi opy ran-4-y1)-4,5,6,7-tetrahy dro-1H-
indazol
carb oxamide,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-1 -((R)-3-hy droxy -3 -
methylbutan-2-y1)-N-(3 -
methyl-1,1 -di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-1-((S)-3 -hy droxy-3-methy
lbutan-2-y1)-N-(3-
methyl-1,1 -di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(3 -(difluoromethoxy)pheny1)-1 -((R)-3-hy droxy -3 -methylbutan-2-y1)-N-
(4-methyl-
1,1-di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazole-6-

carboxamide,
(R)-3 -(3 -(difluoromethoxy)pheny1)-14(S)-3-hy droxy-3 -methylbutan-2-y1)-N-(4-
methyl-
1,1-di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazole-6-

carb ox ami de,
(R)-3 -(5 -fluoro-2-(2,2,2-trifluoroethoxy)pyri din-4-y1)-1-((R)-3 -hy droxy-3-
methy lbutan-
2-y1)-N-((S)-3 -m ethy1-1,1-di ON dotetrahydrothi oph en-3-y 0-4,5,6,7-tetrahy
dro-1 H-
indazole-6-carboxamide,
(R)-3 -(5 -fluoro-2-(2,2,2-trifluoroethoxy)pyri din-4-y1)-1-((S)-3-hy droxy -3-
methylbutan-2-
y1)-N-((S)-3 -methy1-1,1-di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy
dro-1H-indazole-
6-carboxamide,
(R)-N-(4-cy ano-1,1 -di oxi dotetrahy dro-2H-thi opy ran-4-y1)-3-(5 -fluoro-2-
(2,2,2-
trifluoroethoxy)pyri din-4-y1)-1 -((R)-3 -hy droxy -3-methylbutan-2-y1)-
4,5,6,7-tetrahy dro-
1H-indazole-6-carboxamide,
(R)-N-(4-cy ano-1,1-di oxi do tetrahy dro-2H-thi opy ran-4-y 0-3-(5-fl uoro-2-
(2,2,2-
trifluoroethoxy)pyri din-4-y1)-1 -((S)-3 -hy droxy-3-methylbutan-2-y1)-4,5,6,7-
tetrahy dro-
1H-indazole-6-carboxamide,
(R)-3 -(5 -(difluo romethoxy)-2-fl uoropheny1)-1-((1R,25)-2-hy droxy cy cl
openty1)-N-(3 -
methyl-1,1 -di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(5 -(difluo romethoxy)-2-fl uoropheny1)-1-((1R,2R)-2-hy droxy cy cl
openty1)-N-(3-
methyl-1,1-d( oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1R-indazol e-6-carb
oxamt de,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-1-((1S,25)-2-hy droxy cy cl op
enty1)-N-(3 -
methyl-1,1 -di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-1-((1S,2R)-2-hy droxy cy cl
openty1)-N-(3 -
methyl-1,1 -di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
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(R)-3 -(5 -(difluo romethoxy)-2-fluoropheny1)-N-(3 -methy1-1,1-di oxidothi
etan-3 -y1)-1-
(methylsulfony1)-4,5,6,7-tetrahy dro-1H-indazole-6-carboxamide,
(R)-1-(cy clopropylsulfony1)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-N-(3-
methy1-1,1-
di oxidothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb oxamide,
3-(3 -(difluoromethoxy)pheny1)-4,4-difluoro-N-((S)-3 -methyl-1,1 -
di oxid otetrahy drothi ophen-3 -y1)-1-(tetrahy dro-2H-py ran-4-y1)-4,5,6,7-
tetrahy dro-1H-
indazole-6-carboxamide,
(R)-3 -(3 -(difluo romethoxy)pheny1)-4,4-difluoro-N-((S)-3 -methyl-1,1 -
di oxidotetrahy drothi ophen-3 -y1)-1 -(tetrahy dro-2H-py ran-4-y1)-4,5,6,7-
tetrahy dro-1H-
indazole-6-carboxamide,
(S)-3-(3 -(difluoromethoxy)pheny1)-4,4-difluoro-N-((S)-3-methy1-1,1 -
di oxidotetrahy drothi ophen-3 -y1)-1-(tetrahy dro-2H-py ran-4-y1)-4,5,6,7-
tetrahy dro-1H-
indazol e-6-carboxami de,
3-(3 -(difluoromethoxy)pheny1)-1-(5 -fluoropyridin-2-y1)-N-(0-3-methy1-1,1-
di oxi dotetrahydrothi oph en-3 -y1)-1,5,6,7-tetrahy dropyran o [3,2-c]
pyrazol e-6-carboxami de,
3-(3 -(difluoromethoxy)pheny1)-1-(5 -fluoropyridin-2-y1)-N-(3-methy1-1,1 -di
oxidothi etan-
3-y1)-1,5,6,7-tetrahy dropy rano [3,2-c] pyrazol e-6-carb oxamide,
3-(3 -(difluoromethoxy)pheny1)-1-is opropyl-N-(3-methy1-1,1-di oxidothi etan-3
-y1)-
1,5,6,7-tetrahy dropyrano [3,2-c] py razol e-6-carboxamide,
(S)-3-(3-(difluoromethoxy)pheny1)-1-is opropyl-N-(3 -methy1-1,1-di
oxidothietan-3 -y1)-
1,5,6,7-tetrahy dropyrano [3,2-c] py razol e-6-carboxamide,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -is opropyl-N-(3-methy1-1,1 -di
oxidothi etan-3-y1)-
1,5,6,7-tetrahy dro pyrano [3,2-c] pyrazole-6-carboxamide,
3-(5 -(difluoromethoxy)-2-fluoropheny1)-1-is opropy 1-N-(3 -methy1-1,1-di oxi
dothi etan-3 -
y1)-1,5,6,7-tetrahydropyrano [3,2-c] pyrazole-6-carboxamide,
3-(5 -(difluoromethoxy)-2-fluoropheny1)-1-is opropyl-N-(0)-3 -methyl-1,1-
di oxidotetrahy drothi ophen-3 -y1)-1,5,6,7-tetrahy dropyrano [3,2-c] pyrazol
e-6-carb oxamide,
3 -(5 -(difluoromethoxy)-2-fluoropheny1)-1-is opropyl-N-((R)-3 -methyl-1,1-
di oxidotetrahy drothi ophen-3 -y1)-1,5,6,7-tetrahv dropyrano [3,2-c] pyrazol
e-6-carb oxamide,
N-(3,3 -difluoro-l-methylcy clobutv1)-3 -(3-(difluoromethoxy)ph eny1)-1-is
opropyl-1,5,6,7-
tetrahy dropyrano [3,2-c] py razol e-6-carboxamide,
(S)-3-(3-cyclopropylpheny1)-1-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-y1)-
1,5,6,7-
tetrahy dropy rano [3,2-c] py razol e-6-carboxamide,
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(R)-3 -(3 -(1 -fluorocy cl opropyl)pheny1)-1 -(4-fluoropheny1)-N-((S)-3 -
methyl-1,1 -
di oxi d otetrahy d rothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami d e,
(R)-3 -(3 -(2-aminopropan-2-yl)pheny1)-1-(4-fluoropheny1)-N-((5)-3 -methyl-1,1
-
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(6-(difluo romethoxy)py razin-2-y1)-1-(5 -fluoropyri din-2-y1)-N-((S)-3-
methy1-1,1-
di oxi d otetrahy d rothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami d e,
(R)-1-(5-fluoropy ri din-2-y1)-N-((5)-3-methy1-1,1-di oxi dotetrahy drothi
ophen-3 -y1)-3-(1 -
methy1-1H-py razol-5-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -is opropyl-N-(py ri din-3 -y lmethyl)-
4,5,6,7-
tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -is opropyl-N-(is oxazol-4-ylmethyl)-
4,5,6,7-
tetrahy dro-1H-indazol e-6-carboxami de,
(6R)-3 -(5-(difluorometh oxy)-2-fl uoropheny1)-1-i sopropyl -N-(1 s opropy1-2-
oxopyrrolidin-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-3 -(3 -(di uorometh oxy)ph eny 1)-N -((S)- 1-hy droxy prop an-2-y1)-1-i s
opropy l -4,5,6,7-
tetrahy dro-1H-indazol e-6-carboxami de,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -is opropyl-N-(1-methoxy -2-
methylpropan-2-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(3 -(difluoromethoxy)pheny1)-N-(5 -methy1-1,3,4-thi adi azol-2-y1)-1-
(tetrahy dro-2H-
py ran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(5 -(difluo romethoxy)pyri din-3-y1)-1-is opropyl-N-(0)-1 -((R)-2 -
methylmorpholino)prop an-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami
de,
(R)-3-(3-(difluoromethoxy )pheny1)-N-(3-ethy1-1,1-dioxidothietan-3-y1)-1-
isopropy 1-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(3 -(difluoromethoxy)pheny1)-N-(2-(1,1-di oxi dothi omorpholino)ethyl)-
1-is opropyl-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(3 -(difluo romethoxy)pheny1)-1 -is opropyl-N-(2-(N-methylsul
famoypethyl)-4,5,6,7-
tetrahy dro-1H-indazol e-6-carboxami de,
(R)-3 -(3 -(chfluoromethoxy )pheny 1)-1 \ -((R)-3 -methy1-1,1-di oxi dotetrahy
drothi ophen-3 -
y1)-1-(1-methy 1piperi din-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami
de,
(R)- 1-acety1-3 -(3 -(difluoromethoxy)pheny1)-N-((S)-3-methy1-1,1 -
di oxi d otetrahy d rothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami d e,
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(R)- 1-(cy cl opropanecarbony1)-3 -(3-(difluoromethoxy)pheny1)-N-((S)-3-methy1-
1,1 -
di oxi d otetrahy d rothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami d e,
(R)-3 -(3 -(difluoromethoxy)pheny 1)-N-((5)-3-methyl-1,1 -di oxi dotetrahy
drothi ophen-3-
y1)-1-(tetrahy dro-2H-pyran-4-carb ony 0-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)- 1-benzoy1-3-(3 -(difluoromethoxy)pheny1)-N-((S)-3 -methyl-1,1-
di oxi d otetrahy d rothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami d e,
(R)-1-benzy1-3-(3-(difluoromethoxy)pheny1)-N-(0)-3-methyl-1,1 -
di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(3 -(difluoromethoxy)pheny1)-N-((S)-3-methy1-1,1 -di oxi dotetrahy
drothi ophen-3-
y1)-1 -((tetrahy dro-2H-py ran-4-yOmethy 0-4,5,6,7-tetrahy dro-1H-indazole-6-
carb oxamide,
(6R)-1-(1-cy anoethyl)-3-(5 -(difluoromethoxy)-2-fluoroph eny1)-N-(3 -methyl-
1,1-
di oxidothi etan-3-y1)-4,5,6,7-tetrahydro-1H-indazol e-6-carboxami de,
(6R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-N-(3 -methyl-1,1 -di oxi dothi
etan-3 -y1)-1 -(1-
(thiazol-2-ypethyl)-4,5,6,7-tetrahydro-1H-indazol e-6-carboxami de,
(R)- 1 s opropyl-N-(3-methy1-1,1-di oxi dothi etan-3 -y1)-3-(3-(1 -
(tri fluoromethyl)cy cl opropyl)pheny1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3 -(3 -(1 -cy ano cy cl opropyl)pheny1)-1 s opropyl-N-(3 -methyl-1,1 -di
oxi dothi etan-3-y1)-
4,5,6,7-tetrahy dro-1H-ind azol e-6- carb oxami de,
(R)-3 -(2-(1,1-difluoroethyl)-5-fluoropy ri din-4-y1)-1 s opropyl-N-(4-methy1-
1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y 0-4,5,6,7-tetrahy dro-1H-in dazol e-6-
carb oxami de,
(R)- 1 s opropyl-N-(3-methy1-1,1-di oxi dothi etan-3 -y1)-3 -(2-methy lbenzo
oxazol-4-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(3 -(cy ano methyl)pheny1)-1-i s opropyl-N-(3 -methyl-1,1 -di oxi dothi
etan-3 -y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(5 -(tert-butyl carb amoyOpyri din-3 -y1)-1-i s opropyl-N-(3 -methy1-
1,1-di oxi dothi etan-
3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3 -(cy anomethoxy)pheny1)-1-i s opropyl-N-(3 -methyl-1,1 -di oxi dothi
etan-3 -y1)-
4,5,6,7-tetrahy dro-111-indazol e-6- carb oxami de,
(R)-3 -(3 -(1H-py razol-1-yl)pheny1)-1 s opropyl-N-(3-methy1-1,1-di oxi dothi
etan-3 -y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-1-is opropyl-N-(3-methy1-1,1-di oxi d othi etan-3 -y1)-3 -(3 -(methyls
ulfonyl)pheny1)-
4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
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(R)-3-(3-(N-ethylsulfamoyl)pheny1)-1-isopropyl-N-(3-methyl-1,1-dioxidothietan-
3-y1)-
4,5,6,7-tetrahydro-1H-indazo1e-6-carboxamide,
(R)-3-(5-ethy1-2-fluoropheny1)-1-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-
y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(5-cyano-2-fluoropheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-3-
y1)-
4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(1,1-difluoroethyl)pheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-
3-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-N -(3 ,3 -difluoro-1-methylcyclobuty1)-3-(3-(1-hydroxycyclobutyl)pheny1)-1-
isopropyl-
4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)pheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-3-
y1)-
1,4,6,7-tetrahy dropyrano14,3-c] py razol e-6-carboxami de,
(S)-3-(3-(difluoromethoxy)pheny1)-1-i sopropyl -N-(3-methy1-1,1 -di oxi dothi
etan -3-y1)-
1,4,6,7-tetrahy dropyrano [4,3-c] py razol e-6-carboxami de,
(R)-3 -(5 -(di fl uo rometh oxy)-2-fl uoroph eny1)-1-i s opropyl -N-(3-methyl -
1,1 -di oxi dothi etan-
3-y1)-1,4,6,7-tetrahydropyrano[4,3 -c] pyrazole-6-carboxamide, or
(R)-3-(5-cyclopropy1-2-fluoropheny1)-1-isopropyl-N-(3-methyl-1,1-
dioxidothietan-3-y1)-
1,4,6,7-tetrahy dropyrano [4,3-c] py razol e-6-carboxami de.
30. The compound of any of claims 1-29, or a pharmaceutically acceptable
salt
thereof, which is
= (7)_...F _N,
F \ rF
F =
I N H I N
N
0 0 0
0 e cff
cp-0,
F F
`Tor
0 4 OH 04 OH
, or
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31. A composition for treating a condition selected from hepatic steatosis,

nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus,
obesity, hyperlipidemia,
hypercholesterolemia, atherosclerosis, cognitive decline, dementia,
cardiorenal diseases and
heart failure comprising a compound of any of claims 1 to 30, or a
pharmaceutically acceptable
salt thereof, and a pharmaceutically carrier.
32. A composition comprising a pharmaceutically acceptable carrier and a
compound
according to any one of claims 1 to 30, or a pharmaceutically acceptable salt
thereof
33. A method for treating a condition selected from hepatic steatosis,
nonalcoholic
steatohepatitis (NASH), fibrosis, 1ype-2 diabetes mellitus, obesity,
hyperlipidemia,
hypercholesterolemia, atherosclerosis, cognitive decline, dementia,
cardiorenal diseases and
heart failure comprising administering to a patient in need thereof of a
therapeutically effective
amount of a compound of any of claims 1 to 30, or a pharmaceutically
acceptable salt thereof
34. Use of a compound of any of claims 1 to 30, or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for treating a
condition selected from
hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, 1ype-2
diabetes mellitus,
obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive
decline, dementia,
cardiorenal diseases and heart failure.
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Description

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TITLE OF THE INVENTION
PREPARATION OF TETRAHYDROINDAZOLE DERIVATIVES AS NOVEL
DIACYLGLYCERIDE 0-ACYLTRANSFERASE 2 INHIBITORS
FIELD OF THE INVENTION
The present invention is directed to novel pharmaceutical compounds which
inhibit
diacylglyceride 0-acyltransferase 2 ("DGAT2"), and may be useful for
preventing, treating or
acting as a reversing agent for hepatic steatosis, nonalcoholic
steatohepatitis (NASH), fibrosis,
type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia,
atherosclerosis,
cognitive decline, dementia, cardiorenal diseases such as chronic kidney
diseases and heart
failure, and related diseases and conditions, as well as methods of making
such compounds and
pharmaceutical compositions comprising such a compound and a pharmaceutical
carrier.
BACKGROUND OF THE INVENTION
Triacylglycerols ("TGs") serve several functions in living organisms. One such
function
of TGs is in the storage of energy. TGs also play a role in the synthesis of
membrane lipids. TG
synthesis in cells may protect them from the potentially toxic effects of
excess fatty acid ("FA").
In enterocytes and hepatocytes, TGs are synthesized for the assembly and
secretion of
lipoproteins which transport FA between tissues. TGs play a role in the skin's
surface water
barrier, and TGs in adipose tissue provide insulation for organisms.
The glycerol phosphate and the monoacylglycerol pathways are the major
pathways for the
biosynthesis of TG. However, the last step in the synthesis of TG involves the
reaction of a fatty
acyl-CoA and diacylglycerol (-DAG") to form TG. The reaction is catalyzed by
acyl-
CoA:diacylglycerol acyltransferase ("DGAT-) enzymes. There have been
identified two DGAT
enzymes, DGAT1 and DGAT2. Although DGAT1 and DGAT2 catalyze the same reaction,
they
differ significantly at the level of DNA and protein sequences. DGAT2 can
utilize endogenous
fatty acid to synthesize TG in in vitro assays, whereas DGAT1 appears to be
more dependent on
exogenous fatty acid (Yen et al., I Lipid Research, 2008, 49, 2283).
Inactivation of DGAT2
impaired cytosolic lipid droplet growth, whereas inactivation of DGAT1 exerts
opposite effect.
(Li et al Arterioscler. Throm.h. Vasc. Bid. 2015, 35, 1080).
DGAT2 is an integral membrane protein of the endoplasmic reticulum and is
expressed
strongly in adipose tissue and the liver. DGAT2 appears to be the dominant
DGAT enzyme
controlling TG homeostasis in vivo. DGAT2 deficient mice survive for only a
few hours after
1
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birth. On the other hand, DGAT1 deficient mice are viable (Yen etal., I Lipid
Research, 2008,
49, 2283).
Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been
mostly
comprehended from effort exploiting anti-sense oligonucleotides (ASO) in
rodents. In this
setting, DGAT2 knockdown in ob/ob mice with a DGAT2 gene-specific ASO resulted
in a dose
dependent decrease in very low density lipoprotein (-VLDL") and a reduction in
plasma TG,
total cholesterol, and ApoB (Liu, et at., Biochim. Biophys Acta 2008, 1781,
97). In the same
study, DGAT2 antisense oligonucleotide treatment of ob/ob mice showed a
decrease in weight
gain, adipose weight and hepatic TG content. Id. In another study, antisense
treatment of ob/ob
mice improved hepatic steatosis and hyperlipidemia (Yu, el al., Hepatology,
2005, 42, 362).
Another study showed that diet-induced hepatic steatosis and insulin
resistance was improved by
knocking down DGAT2 in rats. These effects seem to be unique to inhibition of
DGAT2, as
ASO against DGAT1 did not lead to similar beneficial effects. Although the
molecular
mechanism behind these observations remains uncertain, the collective data
suggest that
suppression of DGAT2 is associated with reduced expression of lipogenic genes
(SREBP1c,
ACC1, SCD1, and mtGPAT) and increased expression of oxidative/thermogenic
genes (CPT1,
UCP2) (Choi et al., I Bio. Chem., 2007, 282, 22678).
In light of the above description, inhibitors of DGAT2 are useful for treating
disease
related to the spectrum of metabolic syndrome such as hepatic steatosis, non-
alcoholic
steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity,
hyperlipidemia,
hypercholesterolemia, atherosclerosis, cognitive decline, dementia,
cardiorenal diseases such as
chronic kidney diseases and heart failure and related diseases and conditions.
DGAT2 inhibitor compounds are described in W02021064590, W02016036633,
W02016036636, W02016036638, W02018093696, W02018093698, W02013150416,
US20150259323, W02015077299, W02017011276, W02018033832, US201801628,
W02003053363.
SUMMARY OF THE INVENTION
The present disclosure is directed to compounds having structural Formula 1:
2
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R1
R4 y'X
I R3 I N
0 R2
or pharmaceutically acceptable salts thereof wherein:
X and Y are independently selected from 0 or C(R5)2, wherein both X and Y are
both not 0; and
R1 is
(1) phenyl unsubstituted or substituted with 1, 2, or 3 R6,
(2) 5- or 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms
independently
selected from N, 0, and S. wherein the heteroaryl is unsubstituted or
substituted
with 1, 2, or 3 R6, or
(3) 8- to 10- membered fused heteroaryl containing 1, 2, 3 heteroatoms
independently selected from N, 0, and S, wherein the heteroaryl is
unsubstituted
or substituted with 1, 2, or 3 R6;
R2 is
(1) phenyl unsubstituted or substituted with 1, 2, or 3 R7,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, 0, and S. wherein the heteroaryl is unsubstituted or
substituted
with 1, 2, or 3 R7,
(3) C1_6alkyl unsubstituted or optionally mono-substituted, disubstituted
or
trisubstituted with halogen, OH, CF3, -CN, or (C3_6)cycloalkyl,
(4) (C3-6)eycloalkyl unsubstituted or optionally mono-substituted,
disubstituted or
trisubstituted with Ci-oalkyl, halogen, OH, CF3, or -CN,
(5) -(C3-6)alkyl-C(0)NH2,
(6) 4- to 6- membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S wherein the heterocyclyl is unsubstituted or
substituted
by 1, 2, or 3 R7,
(7) -CH2-heteroaryl unsubstituted or substituted by 1, 2, or 3 R7,
(8) -CH2-aryl unsubstituted or substituted by 1, 2, or 3 R7,
(9) -CH2-heterocyclyl unsubstituted or substituted by 1, 2, or 3 R7,
(10) -C(=0) (C1-6)alkyl unsubstituted or substituted with 1, 2, or 3 R7,
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(11) -C(=0) (C3-6)cycloalkyl unsubstituted or substituted with 1, 2, or 3
R7,
(12) -C(=0) (CI-6)heterocyclylunsubstituted or substituted with 1, 2, or 3 R7,
(13) -C(=0) aryl unsubstituted or substituted with 1, 2, or 3 R7,
(14) -S02(C1-6)alkyl unsubstituted or substituted with 1, 2, or 3 R7,
(15) -S02(C3-6)cycloalkyl unsubstituted or substituted with 1, 2, or 3 R7'
(16) -S02-aryl unsubstituted or substituted with 1, 2, or 3
R7,
R3 is
(1) 4- to 7-membered heterocyclyl containing 1 or 2
heteroatoms independently
selected from N, 0 and S,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, 0, and S.
(3) -(C1-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered
heteroaryl
containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S,
(4) -(Ci-6)alkyl-aryl,
(5) -(CI-6)alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S,
(6) -(C1-6)alkyl,
(7) -(C3-6)cycloalkyl,
(8) -(C3_6)cycloalkyl-heterocyclyl wherein the heterocyclyl is a 3-to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S,
(9) -(C1-6)hydroxyalkyl,
(10) -(C1-6)alkyl-S(0)2-NRgaRgb,
(11) -(C1-6)alky 1-S (0)2-(C1-3)alky 1,
(12) -(C1-3)alkyl-heteroaryl, wherein the heteroaryl is an 8- to 10- membered
fused
ring, and wherein the heteroaryl contains 1, 2, 3, or 4 heteroatoms
independently
selected from N, 0, and S,
(13) -(C1-6)alkyl-SONH-(C1-3)alkyl,
(14) -(C1-6)alkyl-(C3-6)cycloalkyl,
(15) fused aryl,
(16) -C(16)alkyl-N(R11)o,
(17) -C(1_6a1ky1)-0-C1_3alkyl, or
(18) -C(1-6)alkyl-O-C3-6cycloalkyl,
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wherein each aryl, fused aryl, heteroaryl, cycloalkyl, or heterocyclyl is
unsubstituted or
substituted with 1, 2, or 3 R9, and wherein each alkyl is unsubstituted or
substituted with 1, 2, or
3 Rio;
R4 is
(1) hydrogen,
(2) (C1-3)alkyl,
or R5 and R4, together with the nitrogen atom to which they are attached,
combine to form a
mono- or bicyclic heterocyclyl ring containing 1 N and optionally containing 1
additional
heteroatoms independently selected from N, 0 and S, wherein the heterocyclyl
ring is
unsubstituted or substituted by 1, 2, or 3 R'';
when present, each R5 is selected from
(1) hydrogen,
(2) halogen, or
(3) cyano;
when present, each R6 is independently selected from
(1) cyano,
(2) halogen,
(3) (C1-6)alkyl or 0C1_6a1ky1 wherein the alkyl moiety is optionally
substituted with
cyano,
(4) (C3-6)cycloalkyl, optionally substituted with halogen, C1-6alkyl, C1-
6haloalkyl,
cyano, OH or OCi-oalkyl,
(5) -C(0)N(R11)2,
(6) (C3-6)cycloalkyloxy wherein the cycloalkyl is optionally substituted
with halogen,
C1-6alkyl, C1-6haloalkyl, cyano, OH, or 0C1-6a1ky1,
(7) hydroxy,
(8) _NRiiRii,
(9) (C1-6)haloalkyl-,
(10) (C1-6)haloalkoxy-,
(11) -S02(C1-6)alkyl,
(12) -SONH(C1-6)alkyl,
(13) C1_6alkyl-NR11R1i; or
(14) 5 membered heteroaryl comprising 2 nitrogen atoms;
when present, each R7 is independently selected from
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(1) (C1-6)alkyl,
(2) halo,
(3) (C1-6)alkoxy-,
(4) (C1-6)haloalkyl-,
(5) (C3-6)cycloalkyl,
(6) C(0)H or -C(0)-0H,
(7) C(0)(C1-6)alkyl or -C(0)0-(C1-6)alkyl,
(8) hydroxy,
(9) CN,
(10) deuterium,
(11) 0C1-3ha10a1ky1, or
(12) oxo;
when present, R8a and R" are independently selected from
(1) hydrogen,
(2) (C1_3)alkyl,
(3) -(C1-3)alkyl-phenyl,
(4) 5- or 6-membered heteroaryl containing 1, 2, or 3
heteroatoms independently
selected from N, 0, and S. or
(5) phenyl;
when present, each R9 is independently selected from
(1) (C1-3)alkyl,
(2) (C1-3)haloalkyl-,
(3) oxo,
(4) (C3-6)cycloalkyl,
(5) -C(0)0-(C1-4)alkyl,
(6) -NR11R11,
(7) hydroxy,
(8) phenyl unsubstituted or substituted with halo,
(9) hydroxy(C1-3)alkyl-,
(10) cyano,
(11) halo,
(12) C(0)C1-6alkyl or C(0)C3-6cycloalkyl,
(13) C(0)NHC1-3a1ky1, or
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(14) 6 membered heterocycle containing one Oxygen and one Nitrogen;
when present, R' is
(1) (C1-3)alkyl,
(2) (C1-3) hydroxy alkyl-,
(3) (C1-3)alkoxy-,
(4) hydroxy,
(5) halogen,
(6) (C1-3)haloalkyl-,
(7) N(R11)2,
(8) (C1-3)alkyl-S-, or
(9) phenyl;
when present, each R11 is independently
(1) hydrogen, or
(2) (C1-6)alkyl;
when present, 1212, R12a and R'211 are independently
(1) hydrogen,
(2) (C1-6)alkyl,
(3) (C3-6)cycloalkyl, or
(4) (C1_6)haloalkyl.
In Embodiment 1 of this disclosure are compounds of Formula I, or a
pharmaceutically
acceptable salt of any of the foregoing, wherein R1 is
a) phenyl substituted with one to three substituents independently selected
from hydroxy,
halogen, hydroxy, CN, C1-3a1ky1, C1-3a1ky1-CN, OC1-3a1ky1-CN, C1-3ha10a1ky1,
C3-
6cyc10a1ky1 -0C1-3alkyl, -0C1-3haloalkyl, -0C3-6cyc10a1ky1, 5 membered
heteroaryl
containing 2 nitrogen atoms, (C3-6)cycloalkyloxy, S(0)2C1-6a1ky1, S(0)2NHC1-
3a1ky1, or
C1-3alkylNH2, and wherein the alkyl moiety is optionally further substituted
with cyano,
wherein the cycloalkyl moiety is optionally further substituted with 1 or two
of the
following: halogen, Ci-6alkyl, C1-6haloalkyl, cyano, OH, or 0C1-6a1ky1;
b) a 6 membered heteroaryl containing one or two nitrogen atoms substituted
with one to
two substituents selected from: halogen, hydroxy, C1-3alkyl, C1_3haloalkyl,
C3_6cycloalky1,
-0C1-3alkyl, -0C1-3haloalkyl, -0-C3-6cycloalkyl, C(0)NC1-6alkyl, or CN, and
wherein the
cycloalkyl moiety is optionally further substituted with 1 or 2 fluoro atoms
or C1-3alkyl,
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c) a 5 membered heteroaryl containing one to three heteroatoms optionally
substituted with
one to two substituents independently selected from with halogen, (C1-3)alkyl,
(C3-
6)cycloalkyl, (C1-3)haloalkyl-, OH or 0C1-3a1ky1; or
d) 8- to 10- membered fused heteroaryl containing at least one nitrogen and
optionally
containing one oxygen optionally substituted with 1 or 2 substituents
independently
selected from halogen, C1-3a1ky1, C1-3haloalkyl, 0C1-3a1k-y1, or 0C1-
3haloalkyl.
In Embodiment 2 of this disclosure are compounds of Formula I, or any one of
Embodiments 1,
or a pharmaceutically acceptable salt of any of the foregoing, wherein 10 is
a) phenyl substituted with one or two substituents selected from: hydroxy.
halogen. CN, Ci-
3a1ky1, C1-3a1ky1-CN, OCI-3a1ky1-CN, C1-3ha10a1ky1, C3-6cyc10a1ky1, -0C1-
3a1ky1, -0C1-
3haloalkyl, -0-cyclopropyl, 5 membered heteroaryl containing 2 nitrogen atoms,
S(0)2Ci-
3a1ky1, S(0)2NHC1-3a1ky1, or C1-3alkylNH2; and wherein the alkyl moiety is
optionally
further substituted with cyano, and wherein the cycloalkyl moiety is
optionally further
substituted with F, CH3, CF3, CN, or OH;
b) a 6 membered heteroaryl containing one or two nitrogen atoms substituted
with one or
two substituents selected from: halogen, hydroxy, Ci-3a1ky1, Ci-3ha10a1ky1, -
0C1-3a1ky1, -
0C1-3ha10a1ky1, -0-cyclopropyl, or C(0)NHC1-6a1ky1, and wherein the cycloalkyl
moiety
is optionally further substituted with 1 or 2 fluoro atoms or CH3;
e) 5 membered heteroaryl containing one to three heteroatoms optionally
substituted with
one to two substituents independently selected from with halogen, or (C1-
3)alkyl; or
d) 9 or 10- membered fused heteroaryl containing at least one nitrogen and
optionally
containing one oxygen atom optionally substituted with 1 or 2 methyl
substituents.
In Embodiment 3 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-2, or a pharmaceutically acceptable salt of any of the foregoing, wherein
is
F N
F ON7....r 4
F 2-"C)
F )¨F
CI
4

0CF340, oj --O
F y
F V
C)\----(F CI F \ F-2F3
F D)r2.3D FINF
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F
F F * 4
ci * Ckr-F _?_ _F) F * c 1 r...2.--0
\.._... ......
)c====F
F F F F
F IP" CN Ho
= F
vir F3C N F F
Fjr
F * * r * / 2 * Cli
,= µF
F N
,
0 N .,( 0 r-CN 0
N
*
N IN ai, 1.0 ,,...õ
s-
4ft
H
NC F
e 14 F = Nr
NH2 N--",\,,,
.,,,,..-=- )--F ,Nfrill ri 0\t". F
-s....-
F =

F=., F ,--
, ,
F . 0 Nii.
, or
In Embodiment 4 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-3 or a pharmaceutically acceptable salt of any of the foregoing, wherein Rl
is phenyl
substituted with a substituent selected from: hydroxy, halogen CN, C13alky1,
C13a1kyl-CN,
0C1-3a1ky1-CN, C1-3ha10a1ky1, C3-6cycloalkyl, -0C1-3a1ky1, -0C1-3ha10a1ky1, -0-
cyclopropyl, 5
membered heteroaryl containing 2 nitrogen atoms, S(0)2C1-3a1ky1, S(0)2NHC1-
3a1ky1, or Ci-
3alkylNH2, and wherein the cycloalkyl moiety is optionally further substituted
with F, CH3, CF3,
CN, or OH.
In Embodiment 5 of this disclosure are compounds of Formula 1, or any one of
Embodiments 1 -
3 or a pharmaceutically acceptable salt of any of the foregoing, wherein 10 is
a 6 membered
heteroaryl containing one or two nitrogen atoms substituted with one or two
substituents selected
from: halogen, C1-3a1ky1, C1-3ha10a1ky1, -0C1-3alkyl, -0C1-3haloalkyl, -0-
cyclopropyl,
C(0)NHC1-6a1ky1, and wherein the cycloalkyl moiety is optionally further
substituted with 1 or 2
fluoro atoms or CH3.
In Embodiment 6 of this disclosure are compounds of Formula 1, or any one of
Embodiments
1-3 or a pharmaceutically acceptable salt of any of the foregoing, wherein Rl
is 5 membered
heteroaryl containing one to three heteroatoms optionally substituted with one
to two
substituents independently selected from with halogen, or (C1-3)alkyl.
In Embodiment 7 of this disclosure are compounds of Formula I, or any one of
Embodiments 1-
3 or a pharmaceutically acceptable salt of any of the foregoing, wherein le is
9 or 10- membered
fused heteroaryl containing one or two heteroatoms independently selected from
nitrogen or
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oxygen optionally substituted with 1 or 2 methyl substituents.
In Embodiment 8 of this disclosure are compounds of Formula I, or any one of
Embodiments 1-
7 or a pharmaceutically acceptable salt of any of the foregoing, wherein R1
N
..) . ). ---\--F 1;1 \ Sr-F F 0 * Nr.-F F i CkrF F-
µ j--....., / 1 \1 [).-C F3 F \ / 1\1 No__
--- F
F F F
or
.
In Embodiment 9 of this disclosure are compounds of Formula I, or any one of
Embodiments 1-
8 or a pharmaceutically acceptable salt of any of the foregoing, wherein R2 is
(1) phenyl unsubstituted or substituted with 1, 2, or 3 R7,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, 0, and S. wherein the heteroaryl is unsubstituted or
substituted
with 1, 2, or 3 R7,
(3) C1-6alkyl unsubstituted or mono-substituted, disubstituted, or
trisubstituted with
halogen, OH, CF3, -CN, deuterium, or (C3-6)cycloalkyl,
(4) (C3-6)cycloalkyl unsubstituted or optionally mono-substituted,
disubstituted or
trisubstituted with C1-6a1ky1, halogen, OH, CF3, or -CN,
(5) -(C3-6)alkylC(0)NH2,
(6) 4- to 6- membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S wherein the heterocyclyl is unsubstituted or
substituted
by 1, 2, or 3 R7,
(7) -CH2-heteroaryl unsubstituted or substituted by 1, 2, or 3 R7,
(8) -CH2-aryl unsubstituted or substituted by 1, 2, or 3 R7,
(9) -CH2-heterocyclyl unsubstituted or substituted by 1, 2, or 3 R7,
(10) -C(=0) (C1-6)alkyl unsubstituted or substituted with 1, 2, or 3 R7,
(11) -C(=0) (C3-6)cycloalkyl unsubstituted or substituted with 1, 2, or 3
R7,
(12) -C(=0) (CI-6)heterocycly1 unsubstituted or substituted with 1, 2, or 3
R7,
(13) -C(=0) aryl unsubstituted or substituted with 1, 2, or 3 R7,
(14) -S02(C1-6)alkyl unsubstituted or substituted with 1, 2, or 3 R7
(15) -S02(C3_6)cycloalkyl unsubstituted or substituted with 1, 2, or 3 R7'
(16) -S02-aryl unsubstituted or substituted with 1, 2, or 3 R7,
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In Embodiment 10 of this disclosure are compounds of Formula I, or Embodiments
1-9, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is
(1) phenyl unsubstituted or substituted with 1, 2, or 3 R7,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N and S, wherein the heteroaryl is unsubstituted or substituted
with
1 or 2 halogen, C1-3alkyl, or cyclopropyl,
(3) Ci-6a1ky1 unsubstituted or mono-substituted, disubstituted, or
trisubstituted with
halogen, OH, CF3, -CN, deuterium, or (C3-6)cycloalkyl,
(4) (C3-6)cycloalkyl unsubstituted or optionally mono-substituted,
disubstituted or
trisubstituted with halogen, C1-6alkyl, OC1-3haloalkyl, OH, CF3, or -CN,
(5) -(C3-6)alkylC(0)NH2,
(6) 4- to 6- membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S wherein the heterocyclyl is unsubstituted or
substituted
with 1 or 2 substituents selected from CH3 or oxo,
(7) -CH2-heteroaryl unsubstituted or substituted with 1 or 2 methyl
substituents,
(8) -CH2-aryl,
(9) -CH2-heterocyclyl,
(10) -C(=0) (C1-6)alkyl,
(11) -C(=0) (C3_6)cycloallcyl,
(12) -C(=0) (C1-6)heterocyclyl,
(13) -C(=0) aryl,
(14) -S02(C1-6)alkyl, or
(15) -S02(C3-6)cycloalkyl.
In Embodiment 11 of this disclosure are compounds of Formula I, or Embodiments
1-10, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is
(1) phenyl unsubstituted or substituted with halogen or OCHF2,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N and S. wherein the heteroaryl is unsubstituted or substituted
with
1 or 2 halogen, C1_3a1ky1, or cyclopropyl,
(3) C1_6a1ky1 unsubstituted or mono-substituted, disubstituted, or
trisubstituted with
halogen, OH, CF3, -CN, deuterium, or (C3-6)cycloalkyl,
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(4) (C3-6)cycloalkyl unsubstituted or optionally mono-substituted,
disubstituted or
trisubstituted with halogen, Ci-6alkyl, OCI-3haloalkyl, OH, CF3, or -CN,
(5) -(C3-6)alkylC(0)NH2,
(6) 4- to 6- membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S wherein the heterocyclyl is unsubstituted or
substituted
with 1 or 2 substituents selected from CH3 or oxo,
(7) -CH2-heteroaryl unsubstituted or substituted with 1 or 2 methyl
substituents,
(8) -CH2-aryl,
(9) -CH2-heterocyclyl,
(10) -C(=0) (Ci-6)alkyl,
(11) -C(=0) (C3-6)cycloalkyl,
(12) -C(=0) (C1-6)heterocyclyl,
(13) -C(=0) aryl,
(14) -S02(C1-6)alkyl, or
(15) -S02(C3-6)cycloalk-yl.
In Embodiment 12 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is phenyl
unsubstituted or substituted with halogen or OCHF2.
In Embodiment 13 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is 5- or 6-
membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected
from N and S,
wherein the heteroaryl is unsubstituted or substituted with 1 or 2 halogen, C1-
3alkyl, or
cyclopropyl.
In Embodiment 14 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is Ci-
6alkyl unsubstituted or optionally mono-substituted, disubstituted, or
trisubstituted with halogen,
OH, CF3, -CN, deuterium, or (C3-6)cycloalkyl.
In Embodiment 15 of this disclosure are compounds of Formula 1, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2is (C3-
6)cycloalkyl unsubstituted or optionally mono-substituted, disubstituted or
trisubstituted with
halogen, C1-6alkyl, OCI-3ha10a1ky1, OH, CF3, or -CN.
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In Embodiment 16 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -(C3-
6)alkylC(0)NH2.
In Embodiment 17 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is 4- to 6-
membered heterocyclyl containing 1 or 2 heteroatoms independently selected
from N, 0 and S
wherein the heterocyclyl is unsubstituted or substituted with 1 or 2
substituents selected from
CH3 or oxo.
In Embodiment 18 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -CH2-
heteroaryl unsubstituted or substituted with 1 or 2 methyl substituents.
In Embodiment 19 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -CH2-
aryl.
In Embodiment 20 of this disclosure are compounds of Formula 1, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -CH2-
heterocyclyl.
In Embodiment 21 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -C(=0)
(C1-6)alkyl.
In Embodiment 22 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -C(=0)
(C3-6)cy cloalky 1.
In Embodiment 23 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -C(=0)
(C1-6)heterocy clyl.
In Embodiment 24 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -C(=0)
aryl.
In Embodiment 25 of this disclosure are compounds of Formula 1, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -
S 02(Ci-6)alky 1 .
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In Embodiment 26 of this disclosure are compounds of Formula I, or Embodiments
1-11, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is -
S02(C3-6)cycloalkyl.
In Embodiment 27 of this disclosure are compounds of Formula I, or Embodiments
1-26, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R2 is
F--Zr(\l/ \ q.µ. * I 'TN.....N
'''bs, IdFil '..NICS
..._
1, F * 05---F C ,
F F , 4.7. ' .....ci
N D n 7eT----.</ .1.---4--
- .7C--4--
OH
'
.,...e. - .,..r 7
44. j1
'''.µ"bõOH OH dbõoH .01 '''Nr....4 ..cpi, ...r ..... 1......
1.......c7
01:s.-S 01.1µ
0
9, S--
,
Co, 0 IIP * -wPC---00
, , or .
In Embodiment 28 of this disclosure are compounds of Formula 1, or Embodiments
1-12, or 27,
or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R2 is
4
F .
In Embodiment 29 of this disclosure are compounds of Formula I, or Embodiments
1-11, 13, or
27, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R2 is
''''F,
F .
In Embodiment 30 of this disclosure are compounds of Formula I, or Embodiments
1-11, 14, or
27, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R2is
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In Embodiment 31 of this disclosure are compounds of Formula I, or Embodiments
1-11, 14, or
27, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R2 is
OH
In Embodiment 32 of this disclosure are compounds of Formula I, or Embodiments
1-11, 14, or
27, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R2 is
OH
In Embodiment 33 of this disclosure are compounds of Formula I, or Embodiments
1-11, 14, or
27, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R2 is
F
In Embodiment 34 of this disclosure are compounds of Formula I, or Embodiments
1-11, 14, or
27, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R2 is
F
In Embodiment 35 of this disclosure are compounds of Formula 1, or any one of
Embodiments
1-34, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is
(1) 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S,
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, 0, and S,
(3) -(Ci-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered
heteroaryl
containing 1, 2, or 3 heteroatoms independently selected from N, 0 and S.
(4) -(C1-6)alkyl-aryl,
(5) -(CI-6)alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S,
(6) -(C1-6)alkyl,
(7) -(C3-6)cycloalkyl,
(g) -(C3 -6 ) cycloalkyl -heterocyclyl wherein the
heterocyclyl is a 3-to 6-membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S,
(9) -(CI-6)hydroxyalkyl,
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(10) -(C1-6)alkyl-S(0)2-NR8aRsb,
(11) -(C i_6)alkyl-S (0)2-(C i_3)alkyl,
(12) -(C1-3)alkyl-heteroaryl, wherein the heteroaryl is an 8- to 10- membered
fused
ring, and wherein the heteroaryl contains 1, 2, 3, or 4 heteroatoms
independently
selected from N, 0, and S,
(13) -(C1-6)alkyl-SONH-(C1-3)alkyl,
(14) -(0-6)alkyl-(C3-6)cycloalkyl,
(15) fused awl,
(16) -C(1-6)alkyl-N(R11)2,
(17) -C(1-6)alkyl-O-C1-3a1ky1, or
(18) -C(1-6)alkyl-O-C3-6cyc10a1ky1,
wherein each aryl, fused aryl, heteroaryl, cycloalkyl, or heterocyclyl is
unsubstituted or
substituted with 1, 2, or 3 R9, and wherein each alkyl is unsubstituted or
substituted with 1, 2, or
3 Rm.
In Embodiment 36 of this disclosure are compounds of Formula 1, or any one of
Embodiments
1-35, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is
(1) 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms
independently
selected from N, 0 and S.
(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms
independently
selected from N, 0, and S,
(3) -(C1-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered
heteroaryl
containing 1, 2, or 3 heteroatoms independently selected from N, 0 and S,
(4) -(Ci-6)alkyl-aryl,
(5) -(C1-6)alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S,
(6) -(Ci-s)alkyl,
(7) -(C3-6)cycloalkyl,
(8) -(C3-6)cycloalkyl-heterocyclyl wherein the heterocyclyl is a 3-to 6-
membered ring
containing 1 or 2 heteroatoms independently selected from N, 0 and S.
(9) -(Ci-6)alkyl-S (0)2-NR 8aR8b,
(10) -C(1_6)alkyl-O-C i_3alkyl, or
(11) -C(1-6)a1kyl-O-C3-6cycloa1kyl,
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wherein each aryl, fused aryl, heteroaryl, cycloalkyl, or heterocyclyl is
unsubstituted or
substituted with 1, 2, or 3 R9, and wherein each alkyl is unsubstituted or
substituted with 1, 2, or
3 Rio.
In Embodiment 37 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is 4-to 7-
membered heterocyclyl containing 1 or 2 heteroatoms independently selected
from N, 0 and S.
wherein the heterocyclyl is unsubstituted or substituted with 1, 2, or 3 R9.
In Embodiment 38 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is a 5- or 6-
membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected
from N, 0, and S,
wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R9.
In Embodiment 39 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is -(C1-6)alkyl-
heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing
1, 2, or 3
heteroatoms independently selected from N, 0 and S, wherein each aryl, fused
aryl, heteroaryl,
cycloalkyl, or heterocyclyl is unsubstituted or substituted with 1, 2, or 3
R9, and wherein each
alkyl is unsubstituted or substituted with 1, 2, or 3 Rm.
In Embodiment 40 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is -(C1_6)alkyl-
aryl, wherein each aryl, fused aryl, or cycloalkyl, is unsubstituted or
substituted with 1, 2, or 3
R9, and wherein each alkyl is unsubstituted or substituted with 1, 2, or 3 Rm.
In Embodiment 41 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is -(C1-6)alkyl-
heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered ring containing 1
or 2 heteroatoms
independently selected from N, 0 and S, wherein each cycloalkyl, or
heterocyclyl is
unsubstituted or substituted with 1, 2, or 3 R9, and wherein each alkyl is
unsubstituted or
substituted with 1, 2, or 3 Rm.
In Embodiment 42 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is -(C1-6)alkyl,
wherein each alkyl is unsubstituted or substituted with 1, 2, or 3 Rm.
In Embodiment 43 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is -(C3-
6)cycloalkyl, wherein each cycloalkyl, is unsubstituted or substituted with 1,
2, or 3 R9.
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In Embodiment 44 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
le is -(C3-
6)cycloalkyl-heterocyclyl wherein the heterocyclyl is a 3-to 6-membered ring
containing 1 or 2
heteroatoms independently selected from N, 0 and S. wherein each cycloalkyl,
or heterocyclyl is
unsubstituted or substituted with 1, 2, or 3 R9, and wherein each alkyl is
unsubstituted or
substituted with 1, 2, or 3 Rm.
In Embodiment 45 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is -(C1-6)alky1-
S(0)2-NR8aR8b, wherein each alkyl is unsubstituted or substituted with 1, 2,
or 3 Rm.
In Embodiment 46 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is -C(1-6)alkyl-O-
C1-3a1ky1 or -C(1-6)alky1-0-C3-6cycloalkyl, and wherein each alkyl is
unsubstituted or substituted
with 1, 2, or 3 RI , and wherein the cycloalkyl is unsubstituted or
substituted with 1, 2, or 3 R9.
In Embodiment 47 of this disclosure are compounds of Formula I, or any one of
Embodiments
1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein
R3 is
N
(3)11 HO
OS' 1
õ4...µ () r--µ 5,.%,
CAA- -5s ,...) s 03_.-. .S
3A
Oni Od.)11. 0 r F-71
...):1..A. Oni
-
,
10-1
Øõ(,,x, oixõ...õ ON ,A
F7 N. * ct-Nµ......) -

F
N ,
N ,Nal
Y--Nd):14, Nql* 1
' ,.Ø....A \ "....
ON ......j. NI,...7rN
- S HO 0 T)
,
0.....Z-N r---N---,A H
// 0 --:p ......) , N .s...^..,..\
0 , 0 , or 0+ % .
In Embodiment 48 of this disclosure are compounds of Formula I, or any one of
Embodiments
ciA
%g
1-38 or 47, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R3 is 8 .
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In Embodiment 49 of this disclosure are compounds of Formula I, or any one of
Embodiments
0.34,$)
1-38 or 47, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R3 is o'
In Embodiment 50 of this disclosure are compounds of Formula I, I-a, or I-b,
or any one of
Embodiments 1-38 or 47, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
64.
05s
R" is o'
In Embodiment 51 of this disclosure are compounds of Formula I, I-a, or I-b,
or any one of
Embodiments 1-38 or 47, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
IV is e
In Embodiment 52 of this disclosure are compounds of Formula 1, I-a, or 1-b,
or Embodiments
1-51, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R4
is H.
In Embodiment 53 of this disclosure are compounds of Formula 1, I-a, or 1-b,
or Embodiments
1-52, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R5
is H, halogen, or CN.
In Embodiment 54 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-53, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R5
is H, F, Cl, or CN.
In Embodiment 55 of this disclosure are compounds of Formula I, or Embodiments
1-54, or a
class thereof, or a pharmaceutically acceptable salt of any of the foregoing,
wherein R6 is
halogen, hydroxy, CN, C1-3a1ky1, C1_3ha10a1ky1, C3-6cycloalkyl, 0C1-3alkyl,
0C1-3haloalkyl, 0C3-
6cyc10a1ky1, S(0)2C1-3alkyl, S(0)2NHC1-3alkyl, C(0)NHC1-3a1ky1, C1-6a1ky1-
NR11R11, or 5
membered heteroaryl with 2 N atoms, and wherein the cycloalkyl is optionally
substituted with
halogen.
In Embodiment 56 of this disclosure are compounds of Formula 1, I-a, or 1-b,
or Embodiments
1-55, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R6
is C1_3alkyl, 0-C3-6cycloalkyl, 0C1-3alkyl, S(0)2C1-3alkyl, S(0)2NHC1-3alkyl,
C(0)NHC1-3alkyl,
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C1_6a1ky1-NR11R11, or 5 membered heteroaryl with 2 N atoms, and wherein the
cycloalkyl is
additionally optionally substituted with 1-3 F.
In Embodiment 57 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-56, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R6
is F, Cl, CHF2, CH3, OCHF2, OCF3, OCH2CH3, OCH(CH3)2, OCF2CHF2, OCH2CHF2,
C(CH3)F2, CH2CN, C(0)NHC(CH3)3, OCH3CN, CH2CH3, CN, C(CH3)2NH2, S(02)CH3,
S(02)NHCH2CH3, OCD2CD3, pyrazolidine, cyclopropyl, cyclobutyl, or 0-
cyclopropyl, and
wherein the cyclopropyl or cyclobutyl is additionally optionally substituted
with one to three
halogen atoms. CN, CF3, or OH.
In Embodiment 58 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-57, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R6
is CH3, OCH2CH3, C(0)NHC(CH3)3, C(CH3)2NH2, S(02)CH3, S(02)NHCH2CH3, OCD2CD3,
pyrazolidine, or 0-cyclopropyl, and wherein the cyclopropyl is additionally
optionally
substituted with one to three halogen atoms. CN, CF3, or OH.
In Embodiment 59 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-58, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R7
is halogen, oxo, C1-6alkyl, 0C1-6ha10a1ky1, CN, deuterium, or C3-6cyc10a1ky1.
In Embodiment 60 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-59, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R7
is F, Cl, oxo, OCHF2, CH3, CN, deuterium, or cyclopropyl.
In Embodiment 61 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-60, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
lea and R81 are independently selected from hydrogen or (C1-3)alkyl.
In Embodiment 62 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-61, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
lea is H.
In Embodiment 63 of this disclosure are compounds of Formula 1, 1-a, or 1-b,
or Embodiments
1-62, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
R8' is H.
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I In Embodiment 64 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-61, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
R8a is CH3.
In Embodiment 65 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-61, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
R8b is CH3.
In Embodiment 66 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-65, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R9
is =0, halogen, OH, Ci-oalkyl, Ci-ohaloalky, C1-3a1ky1-CN, C(0)Ci-oalkyl,
C(0)C3-6cycloalkyl,
C(0)C1-3alkylOH, C(0)NHC1-3alkyl, C1-6alkylOH, or a 6 membered heterocycle
containing one
Oxygen and one Nitrogen atom.
In Embodiment 67 of this disclosure are compounds of Formula 1, I-a, or I-b,
or Embodiments
1-66, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein R9
is =0, CH3, CH2CH3, F, CF3, CH3CN, C(0)cyclopropyl, C(0)EtO, CH(CH3)2, or
C(0)NHCH(CH3)2, or a 6 membered heterocycle containing one Oxygen and one
Nitrogen atom.
In Embodiment 68 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-67, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
Rl is =0, halogen, OH, C1-6a1ky1, Ci-6haloalky, or Ci-6a1kyl0H.
In Embodiment 69 of this disclosure are compounds of Formula I, I-a, or I-b,
or Embodiments
1-68, or a class thereof, or a pharmaceutically acceptable salt of any of the
foregoing, wherein
R' is OH, CH3, or OCH3.
In Embodiment 70 of this disclosure are compounds of Formula or any one of
Embodiments 1-
69, or a pharmaceutically acceptable salt of any of the foregoing, wherein X
and Y are C(R5).
In Embodiment 71 of this disclosure are compounds of Formula or any one of
Embodiments 1-
69, or a pharmaceutically acceptable salt of any of the foregoing, wherein X
is 0, and Y is C(R5)
In Embodiment 72 of this disclosure are compounds of Formula or any one of
Embodiments I-
69, or a pharmaceutically acceptable salt of any of the foregoing, wherein X
is C(R5), and Y is
0.
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In Embodiment 73, the present invention provides a compound as described in
any one of
Examples 1-128 as set forth below, or a pharmaceutically acceptable salt
thereof
In Embodiment 74 of the invention, the compound of formula I, or a
pharmaceutically
acceptable salt thereof, is:
3 -(2-chl oropheny1)-1-(4-fluorophenv1)-N4S)-3-methyl -1, 1-di oxi dotetrahy
drothi ophen-3 -y1)-
4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(S)-3-(2-chloropheny1)-1-(4-fluoropheny1)-N-((5)-3-methyl-1,1-
dioxidotetrahydrothiophen-3-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(2-chloropheny1)-1-(4-fluoropheny1)-N-((5)-3-methyl-1,1-
dioxidotetrahydrothiophen-3-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3-(difluoromethoxy)pheny1)-1 -(4-fluoropheny1)-N- ((S)-3-methyl- 1,1-
di oxi dotetrahydrothi ophen-3-y1)-4,5,6,7-tetrahydro-1H-indazol e-6-carboxami
de,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-((S)-3-methy1-1,1-

di ox i dotetrahydrothi ophen-3-y1)-4,5,6,7-tetrahydro-1H-indazol e-6-
carboxami de,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-(3-methy1-1,1-
dioxidothietan-3-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
1 -(5 -cy cl opropy1-1,3,4-thi adi azol-2-y1)-3-(5 -(difluoromethoxy)pyridin-3
-y1)-N-((S)-3 -methyl-
1,1-di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami d e,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-((R)-3-
methyltetrahydrofuran-3-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-((5)-3-
methyltetrahydrofuran-3-
y1)-4,5,6,7 -tetrahy dro-1H-indazole-6-carboxamide,
(R)-N-(3,3-difluoro-1-methylcyclobuty1)-3-(3-(difluoromethoxy)pheny1)-1-(5-
fluoropyridin-2-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-N4R)-3,3-difluoro-1-(hydroxymethyl)cyclopenty1)-3-(3-
(difluoromethoxy)pheny1)-1-(5-
fluoropyridin-2-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-N-((5)-3,3-difluoro-1-(hydroxymethyl)cyclopenty1)-3-(3-
(difluoromethoxy)pheny1)-1-(5-
fluoropyri din-2-y1)-4,5 ,6,7-tetrahy dro-IR-indazol e-6-carboxami de,
(R)-3-(3-(difluoromethoxy)pheny1)-1-(3,5-difluoropyridin-2-y1)-N-(3-methy1-1,1-
dioxidothietan-
3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
1-(5-chloropyrimidin-2-y1)-3-(3-(difluoromethoxy)pheny1)-N-((S)-3-methy1-1,1-
dioxidotetrahydrothiophen-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
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((R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-1-(3,5-difluoropy ri din-2-y1)-N-
(3 -methyl-1,1 -
di oxi d othi etan-3-y1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3 -(5 -(difluoromethoxy)pyri din-3 -y1)-1-(5 -fluoropy ri din-2-y1)-N-(3 -
methyl-1,1 -
di oxi dothi etan-3-y 0-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3 -(3 -(3,3 -difluoro cy cl obutyl)pheny1)-1-(4-fluoropheny1)-N-((5)-3 -
methyl-1,1-
di oxi d otetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(difluoromethoxy)pyri din-3-y1)-1-(5 -fluoropy ri din-2-y 1)-N-((5)-3-
methyl-1,1 -
di oxi dotetrahy drothi ophen-3-y 0-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-N-0)-3 -cy anotetrahy drofuran-3 -y1)-3-(5-(difluoromethoxy)py ri din-3 -
y1)-1-(5 -
fluoropyridin-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-N -((R)-3-cy anotetrahy drofuran-3 -y 0-3-(5 -(difluoromethoxy)pyri din-3-
y1)-1-(5-
fluoropyri din-2-y1)-4,5.6,7-tetrahy dro-1H-indazol e-6-carboxami
3 -(3 -(difl uorometh oxy)ph eny1)-1 -(5-fluoropyri din-2-y1)-N-((1R,2R)-2-
morpholinocycl openty1)-
4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3-(2-(difluoromethoxy)-5-fluoropyri din-4-y1)-1 sopropyl -N-(4-methyl -1,1
-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3 -(2-ethoxy-5 -fluoropyri din-4-y1)-1-is opropyl-N-(4-methy1-1 ,1 oxi
dotetrahy dro-2H-
thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3-(difluoromethoxy)pheny1)-N-(3-methy1-1,1-di oxidothi etan-3 -y1)-1-
(tetrahy dro-2H-
pyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3-(difluoromethoxy)pheny1)-1 -(1,1-di oxi dotetrahy dro-2H-thi opyran-
4-y1)-N-((5)-3 -
methyl-1,1 -di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol
e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-1 -is o pro pyl-N-((5)-3 -methyl-1,1 oxi
dotetrahy drothi o phen-
3 -y 0-4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-1-is opropyl-N-(3-methy1-1,1-dioxi dothi
etan-3-y1)-4,5,6,7-
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-1 -(tetrahy dro-2H-py ran-4-y1)-N-(2-(6-
(trifluoromethyl)pyri din-3-yl)propan-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
c arb oxami de,
(R)-3-(5-(difluoromethoxy )-2-fluoropheny1)-1-isopropyl-/V-((S)-3-methy 1-1,1-
di oxi dotetrahy drothi ophen-3-y1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-1-is opropyl-N-((R)-3 -methyl-1,1-

di oxi d otetrahy drothi ophen-3-y1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
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(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-1-isopropyl-N-(4-methyl- 1,1 -di
oxi dotetrahy dro-2H-
thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)pheny1)-1-isopropyl-N-(4-methy1-1,1-dioxidotetrahy
dro-2H-
thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3 -cy cl opropoxy pheny1)-1-isopropyl-N-(4-methyl- 1 ,1 -di oxi
dotetrahy dro-2H-thi opy ran-4-
y1)-4,5,6,7 -tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3 -ethoxypheny1)-1-isopropyl-N-(4-methyl-1, 1-di oxi dotetrahy dro-2H-
thi opy ran-4-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(2-ethoxy-5 -fluoropyri din-4-y1)-1-isopropyl-N-(3-methyl- 1 ,1 -di oxi
dothi etan-3-y1)-4,5,6, 7-
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-1-i s opropyl-N-(0-3-methy1-1,1-di oxi dotetrahy drothi ophen-3-y1)-3-(3 -
(2,2,2-
trifluoroethoxy)pheny1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-1 -is opropyl-N-(4-methyl -1,1 -di ox dotetrahydro-2H-thi opyran -4-y1)-3-
(3 -(1,1,2,2-
tetrafluoro ethoxy)pheny1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3-(2-cycl opropoxy -5 uoropy ri din -4-y1)-1-i s opropyl-N-(4-m ethy1-1,1-
di ox i dotetrahy dro-
2H-thi opy ran-4-y1)-4,5,6,7-tetrahy dro -1H-indazol e-6-carb oxami de,
(R)-3 -(5 -fl uoro-2-i soprop oxypy ri din-4-y1)-1-isopropyl-N-(4-methyl-1, 1 -
di oxi dotetrahy dro-2H-
thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(5 -chl oro-2-ethoxypy ri din-4-y1)-1-i s opropyl-N-(4-methy1-1,1 -di
oxi dotetrahy dro-2H-
thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(2-(2,2-difluoro ethoxy)-5 -fl uoropy ri din-4-y1)-1-i s opropyl-N-(4-
methy1-1,1-
di oxi dotetrahy dro-2H-thi opyran-4 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3 -(2-(difluoromethoxy)-5 -fluor py ri din-4-y1)-1 s o pro pyl-N-((5)-3 -
methyl-1,1 -
di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3-(5-(difluoromethoxy)-2-(difluoromethyl)pyridin-3-y1)-1-isopropyl-N-(4-
methy1-1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3 -(5-fl uoro-2-(2,2,2-trifluoroethoxy )py ri din-4-y1)-1 s opropyl-N-(3-
methy1-1,1 -
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3-(5-fluoro-2-(2,2,2-tnfluoroethoxy )py n dm-4-y1)-1-isopropyl-PV-((S)-3-
methyl- 1,1-
di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(5-fl uoro-2-(2,2,2-trifluoroethoxy )py ri din-4-y1)-1 -is opropyl-N-(4-
methy1-1,1 -
di oxi d otetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami d e,
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(R)-3 -(5-(difluoromethoxy)-2-fluoropheny1)-N-(4-methyl-1,1-di oxi dotetrahy
dro -2H-thi opy ran-4-
y1)-1 -(propan-2-yl-d7)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(2-ethoxy-5-fluoropyri din-4-y1)-N-(4-methy1-1,1-di oxi dotetrahy dro-
2H-thi opyran-4-y1)-1-
(propan-2-y 1-d7)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb ox ami de,
(R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-1 - ((R)- 1,1-difluoroprop an-2-y1)-
N-(3-methy1-1,1-
di oxi d othi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3 -(5-(difluoromethoxy)-2-fluoropheny1)-1-((S)-1,1-difluoroprop an-2-y1)-N-
(3-methy1-1,1-
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-1 - ((R) - 1,1-difluoroprop an-2-
y1)-N-(4-methy1-1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3 -(5-(difluoromethoxy)-2-fluoropheny1)-1-(0-1,1-difluoroprop an-2-y1)-N-
(4-methy1-1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3-(2-(ethoxy-d5)-5-fluoropyridin-4-y1)-1-isopropyl-N-(4-methyl-1 ,1-di ox
dotetrahydro-2H-
thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R) -N - (4 - cy an o-1,1 -di ox i dotetrahydro-2H-thi opyran-4-y1)-3-(5-(di
fl uorometh oxy)-2-
fluoropheny1)-1-(prop an-2-yl-d7)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami
de,
(R)-N-(4-cy an o-1,1 -di oxi dotetrahy dro-2H-thiopyran-4-y 0-3-(5-
(difluoromethoxy)-2-
fluoropheny1)-1-is opropy1-4,5,6,7-tetrahy dro-1H-indazole-6-carb oxami de,
(R)-3 -(2-ethoxy-5-fluoropyri din-4-y1)-N-(4-methy1-1,1-di oxi dotetrahy dro-
2H-thi opyran-4-y1)-1-
((R)- 1 ,1 ,1 -trifluoropropan-2-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(2-ethoxy-5-fluoropyri din-4-y1)-N-(4-methy1-1,1-di oxi dotetrahy dro-
2H-thi opyran-4-y1)-1-
(0-1,1,1 -trifluoroprop an-2-y1)-4,5,6,7-tetrahy dro-1H-ind azol e-6-carb
oxami de,
(R)-3 -(5 -ethoxy-2-fluoro pheny1)-1-i s o pro pyl-N-(4-methy1-1,1-di oxi
dotetrahy dro-2H-thi o py ran-
4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(R)- 1 s opropyl-N-(4-methy1-1,1-di oxi dotetrahy dro-2H-thi opy ran-4-y1)-3-
(3 -
(trifluorometh oxy)pheny1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)-3 -(5 -(difluoromethoxy)pyri din-3-y1)-1-isopropyl-N-(4-methyl- 1,1-di oxi
dotetrahy dro-2H-
thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-1-cyclobuty1-3-(5-(difluoromethoxy )-2-fluoropheny1)-N-(3 -methy1-1,1-
dioxi dothi etan-3-y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)- 1 - ((R)- 1-cy cl opropyl ethyl)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-
N-(3 -methyl-1,1-
di oxi d othi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
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(R)- 1 -((S)-1 -cy cl opropyl ethyl)-3-(5 -(difluoromethoxy)-2-fluo ropheny1)-
N-(3 -methyl- 1, 1 -
di oxi d othi etan-3-y1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
ethyl 3 -((R)-3-(5-(difluoromethoxy)-2-fluoropheny1)- 1-i s opro py1-4,5,6,7-
tetrahy dro-1H-
indazol e-6-carboxami do)-3 -methylpyrroli dine- 1 -carboxylate,
(6R)-3-(5-(difluoromethoxy)-2-fluoropheny1)- 1-is opropyl-N-(1 -(is
opropylcarbamoy1)-3 -
methy 1pyrroli din-3 -y1)-4,5,6,7-tetrahy dro- 1H-indazol e-6-carboxami d e,
(6R)-N-(1 -(cy cl oprop anecarbony1)-3 -methylpyrroli din-3-y1)-3-(5-
(difluoromethoxy)-2-
fluoropheny1)- 1 -is opropy1-4,5,6,7-tetrahy dro-1H-indazole-6-carb oxami de,
(R)-3 -(2-fluoro-5-is oprop oxypheny1)- 1 -is opropy l-N-(3-methyl- 1, 1 -di
oxi dothi etan-3-y1)-4,5,6,7-
1 0 tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)- 1 -is opropyl-N-(3-methyl- 1, 1 -
di oxi dothi etan-3 -y1)-
4,5,6,7-tetrahy dro- 1H-indazol e-6-carboxami de,
(R)-3 -(5 -cy cl opropy1-2-fl uoroph eny1)- 1 s opropyl-A43 -m ethyl -1 ,1 -di
oxi dothi etan-3-y1)-4,5,6,7-
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3-(2-chloro-5-(di fl uorometh oxy)ph eny1)- 1 s opropyl-N-(3 -m ethyl - 1
, 1 -di ON i dothi etan -3-y1)-
4,5,6,7-tetrahy dro- 1H-indazol e-6-carb oxami de,
(R)-3 -(5 -cy cl opropoxy -2-fluoroph eny1)- 1 -is opropyl-N-(3-methyl- 1, 1 -
di oxi dothi et an-3 -y1)-
4,5,6,7-tetrahy dro- 1H-indazol e-6-carb oxami de,
(R)-3 -(5 -(difluoromethoxy)-2-methylpy ri din-3-y1)- 1 -is opropyl-N-(3-
methy1-1, 1 -di oxidothi etan-
3 -y1)-4,5,6,7-tetrahy dro- 1H-indazol e-6- carb oxami de,
(R)-3 -(5 -ethoxy -2,3-difluoropheny1)-1 -is opropyl-N-(3-methy1-1, 1 -di oxi
dothi etan-3
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(2-chl oro-5 -(trifl uoromethoxy )py ri din-3-y1)- 1 -is opropy l-N-(3-
methyl- 1, 1 -di oxi do thi elan-
3 -y1)-4,5,6,7-tetrahy dro- 1H-indazol e-6- carb oxami de,
(R)-N-(3,3-difluoro- 1 -methyl cy cl obuty1)-3-(5-(difluoromethoxy)-2-
methylpyri din-3-y1)- 1 -
is opropy1-4,5 ,6,7-tetrahy dro- 1H-indazol e-6-carboxami de,
(R)- 1 s opropyl-N-(3-methyl- 1, 1 -di oxi dothi etan-3-y1)-3 -(5-(1, 1,2,2-
tetrafluoroethoxy)pyri din-3-
y1)-4,5,6,7 -tetrahy dro-1H-indazol e-6-carb oxami de,
(R)- 1-1 s opropyl-N-((S)-3-methyl- 1, 1 -di oxi dotetrahy drothi ophen-3 -y1)-
345 -( 1, 1,2,2-
3 0 tetrafluoro ethoxy)py ri din-3 -y1)-4,5,6,7-tetrahy dro-1H-indazole-6-
carb oxamide,
(R)- 1 s opropyl-N-(4-methy1-1, 1-di oxi dotetrahy dro-2H-thi opy ran-4-y1)-3-
(5-(1, 1,2,2-
tetrafluoro ethoxy)py ri din-3 -y1)-4,5,6,7-tetrahy dro-1H-ind azole-6-carb
oxamid e,
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(R)-3 -(5 -fl uoro-2-(2,2,2-trifluoroethoxy )py ri din-4-y1)-1-((R)-3 -hy
droxy-3-methy lbutan-2-y1)-N-
(4-methyl-LI-di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-IH-
indazol e-6-
carboxami de,
(R)-3 -(5 -fl uoro-2-(2,2,2-trifluoroethoxy )py ri din-4-y1)-14(S)-3-hy droxy-
3-methylbutan-2-y1)-N-
(4-methyl-I ,1-di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-IH-
indazol e-6-
carboxami de,
(R)-3 -(2-ethoxy-5 -fluoropyri din-4-y1)-1-((R)-3 -hy droxy -3-methylbutan-2-
y1)-N-((5)-3-methyl-
1 ,1-di oxi dotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-IH-indazol e-6-
carb oxami de,
(R)-3 -(2-ethoxy-5 -fluoropyri din-4-y1)-1-((S)-3 -hy droxy -3 -methylbutan-2-
y1)-N-((S)-3-methyl-
1,1-dioxidotetrahy drothiophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazole-6-
carboxamide,
(R)-3 -(2-ethoxy-5 -fluoropyri din-4-y1)-1-((R)-3 -hy droxy -3-methylbutan-2-
y1)-N-(4-methy1-1,1 -
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3 -(2-eth oxy-5 -fl uoropyri din-4-y1)-1-((S)-3 -hy droxy -3 -methyl butan-
2-y1)-N-(4-methy1-1,1 -
di oxi dotetrahy dro-2H-thi opyran-4 -y1)-4,5,6,7-tetrahy dro- IH-indazol e-6-
carb oxami de,
(R)-3 -(5 -(di fl uorometh oxy)-2-fl uoroph eny1)-14(R)-3 -hy droxy-3 -m ethyl
butan-2-y1)-N-(3-
methyl-1,1 -di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carboxami de,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-1-((S)-3-hy droxy-3-methy lbutan-
2-y1)-N-(3-methyl-
1,1-di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-1 -((R)-3-hy droxy -3-methylbutan-2-y1)-N-
(4-methy1-1,1 -
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)-3-(3-(difluoromethoxy)ph eny1)-1 -((5)-3 -hy droxy-3-methy lbutan-2-y1)-N-
(4-methyl- 1 ,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro- IH-indazol e-6-
carb oxami de,
(R)-3 -(5 -fl uoro-2-(2,2,2-trifluoroethoxy )py ri din-4-y1)-1-((R)-3 -hy
droxy-3-methy lbutan-2-y1)-N-
((5)-3-methyl-1,1 -di oxidotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-1H-
indazol e-6-
carboxami de,
(R)-3 -(5 -fl uoro-2-(2,2,2-trifluoroethoxy )py ri din-4-y1)-1-(0-3-hy droxy-3-
methy lbutan-2-y1)-N-
((5)-3-methyl-1,1 -di oxidotetrahy drothi ophen-3 -y1)-4,5,6,7-tetrahy dro-IH-
indazol e-6-
carboxami de,
(R)-1V-(4-cy an o-1,1-dt oxi dotetrahy dro-2H-thlopyran-4-y1)-3-(5-fl uoro-2-
(2,2,2-
trifluoroethoxy)pyridin-4-y1)-1-((R)-3-hydroxy -3 -methy lbutan-2-y1)-4,5,6,7-
tetrahy dro-1H-
indazol e-6-carb oxami de,
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(R)-N-(4-cy an o-1,1 -di oxi dotetrahy dro-2H-thiopyran-4-y1)-3-(5-fluoro-2-
(2,2,2-
trifluoro ethoxy)py ri din-4-y1)-1 -((S)-3-hy droxy-3-methylbutan-2-y1)-
4,5,6,7-tetrahy dro-1H-
indazol e-6-carb oxami de,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-1-((1R,25)-2-hy droxy cy cl
openty1)-N-(3 -methyl-1,1 -
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-1-((lR,2R)-2-hydroxy cyclopenty1)-N-
(3-methyl-
1,1-di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-1-((1S,28)-2-hy droxy cy cl op
enty1)-N-(3 -methyl-1,1-
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-14(1S,2R)-2-hy droxy cy
clopenty1)-N-(3 -methyl-1,1 -
di oxi dothi etan-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxamide,
(R)-3 -(5 -(difluoromethoxy)-2-fluoropheny1)-N-(3-methy1-1,1-di oxi dothi etan-
3-y1)-1-
(m ethyl sul fony1)-4,5,6,7-tetrahy dro-1H-in dazol e-6-carboxami de,
(R)-1-(cy cl opropylsulfony1)-3 -(5-(difluoromethoxy)-2-fluoropheny1)-N-(3-
methy1-1,1-
di oxi dothi etan-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxami de,
3 -(3 -(difluoromethoxy)pheny1)-4,4-difluoro-N-(0-3 -methyl-1,1-di oxi
dotetrahy drothi ophen-3 -
y1)-1-(tetrahy dro-2H-pyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazole-6-carb oxami
de,
(R)-3 -(3-(difluoromethoxy)pheny1)-4,4-difluoro-N-((5)-3 -methyl-1,1 -di oxi
dotetrahy drothi ophen-
3 -y1)-1 -(tetrahy dro-2H-py ran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami d e,
(5)-3-(3-(difluoromethoxy)pheny1)-4,4-difluoro-N-((5)-3-methyl-1,1 -
di oxi dotetrahy drothi ophen-3-y1)-1-(tetrahy dro-2H-py ran-4-y1)-4,5,6,7-
tetrahy dro-1H-indazol e-6-
carboxami de,
3 -(3 -(difluoromethoxy)pheny1)-1 -(5-fluoro pyri din-2-y1)-N-(0-3-methy1-1,1 -

di oxi dotetrahy drothi ophen-3-y1)-1,5,6,7-tetrahy dropyrano [3,2-c] py razol
e-6-carboxami de,
3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-(3-methy1-1,1-
dioxidothietan-3-y1)-
1,5,6,7-tetrahy dropy rano [3,2-c] pyrazol e-6-carb oxami de,
3 -(3 -(difluoromethoxy)pheny1)-1 -is opropyl-N-(3-methy1-1,1 -di oxi dothi
etan-3 -y1)-1 ,5,6,7-
tetrahy dropy ran o [3,2-c] py razol e-6-carb oxami de,
(S)-3-(3-(difluoromethoxy )pheny1)-1-is opropyl-N-(3 -methy1-1,1-di oxi dothi
etan-3 -y1)-1,5,6,7-
tetrahy dropyran o [3,2-c] py razol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-1 -is opropyl-N-(3-methy1-1,1-dioxi dothi
etan-3-y1)-1,5,6,7-
tetrahy dropyran o [3,2-c] py razol e-6-carb oxami d e,
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3 -(5 -(difluoromethoxy)-2-fluoro pheny1)-1-isopropyl-N-(3 -methyl-1,1 -di oxi
dothi etan-3-y1)-
1,5,6,7-tetrahydropyrano [3,2-c] pyrazole-6-carboxami de,
3 -(5 -(difluoromethoxy)-2-fluoro pheny1)-1-isopropyl-N-((5)-3-methyl- 1,1-
di oxi dotetrahy drothi ophen-3-y1)-1,5,6,7-tetrahy dropyrano [3,2-c] py razol
e-6-carboxami de,
3 -(5 -(difluoromethoxy)-2-fluoro pheny1)-1-is opropyl-N-((R)-3 -methyl-1,1-
di oxi d otetrahy drothi ophen-3-y1)-1,5,6,7-tetrahy dropyrano [3,2-c] py
razol e-6-carboxami de,
N-(3,3 -difluoro-l-methyl cy cl obuty1)-3-(3 -(difluoromethoxy)pheny1)-1-is
opropyl-1,5,6,7-
tetrahy dropy ran o [3,2-c] py razol e-6-carb oxami de,
(S)-3-(3-cy cl opropy 1pheny1)-1-is opropyl-N-(3 -methy1-1,1-di oxi dothi etan-
3-y1)-1,5,6,7-
tetrahy dropy ran o [3,2-c] py razol e-6-carb oxami de,
(R)-3 -(3-(1-fluorocy cl opropy 1)pheny1)-1-(4-fluoropheny1)-N-((5)-3 -methyl-
1,1-
di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3 -(3-(2-ami nopropan-2-yl)pheny1)-1-(4-fl uoropheny1)-N-((5)-3 -methyl -
1,1-
di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3-(6-(difluoromethoxy)pyrazin-2-y1)-1-(5-fluoropyridin-2-y1)-N-((S)-3-
methy1 -1,1-
di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)- 1 -(5 -fluoropy ri din-2-y1)-N-((5)-3-methyl-1,1 -di oxi dotetrahy drothi
ophen-3-y1)-3-(1 -methyl-
1H-py razol-5 -y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3 -(difluoromethoxy)pheny1)-1-is opropyl-N-(pyri din-3 -ylmethy 0-
4,5,6,7-tetrahy dro-1 H-
indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)pheny1)-1-isopropyl-N-(isoxazol-4-ylmethyl)-4,5,6,7-
tetrahydro- 1 H -
indazol e-6-carb oxami de,
(6R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-1-isopropyl-N-(1-isopropy1-2-
oxopyrrolidin-3-y1)-
4,5,6,7-tetrahydro-1H-indazol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-N-((5)-1-hy droxyprop an-2-y1)-1-is opropy1-
4,5,6,7-
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-1-is opropy 1-N-(1 -methoxy-2-methy 1prop
an-2-y1)-4,5,6,7-
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3-(3-(difluoromethoxy )pheny1)-1\1-(5 -methy1-1,3,4-thiadiazol-2-y1)-1-
(tetrahy dro-211-pyran-
4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(5 -(difluoromethoxy)pyri din-3-y1)-1-is opropyl-N-((.5)-1-((R)-2-methy
lmorpholino)propan-
2-y1)-4,5,6,7-tetrahy dro-1H-indazole-6- carboxamide,
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(R)-3 -(3-(difluoromethoxy)pheny1)-N-(3-ethy1-1,1-di oxi dothi etan-3-y1)-1-is
opropy1-4,5,6,7-
tetrahy dro-1H-ind azol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-N-(2-(1,1 -di oxi dothiomorpholino)ethyl)-1-
is opropy1-4,5,6,7-
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-1 -is opropy 1-N-(2-(N-methylsulfamoyl)
ethyl)-4,5,6,7-
tetrahy dro-1H-ind azol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-N-((R)-3-methyl-1 ,1-di oxid otetrahy
drothi ophen-3-y1)-1 -(1 -
methy 1piperi din-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carboxami de,
(R)- 1-acetyl-3 -(3-(difluoromethoxy)pheny1)-N-((5)-3 -methyl-1,1 -di oxi
dotetrahy drothi ophen-3-
y1)-4,5,6,7 -tetrahy dro-1H-indazole-6-carboxamide,
(R)- 1-(cy cl opropanecarbony1)-3-(3 -(difluoromethoxy)pheny1)-N-((S)-3 -
methyl-1,1 -
di oxi dotetrahy drothi ophen-3-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)-3-(3-(difluoromethoxy)pheny1)-N-((S)-3-methyl-1,1-di oxidotetrahydrothi
oph en-3 -y1)-1-
(tetrahy dro-2H-py ran-4-carbony1)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(R)- 1-b en zoy1-3-(3 -(di fl uorom eth oxy)ph eny1)-N-((S)-3-rn ethyl -1,1-di
oxidotetrahydrothi oph en-3 -
y1)-4,5,6,7 -tetrahy dro-1H-indazol e-6-carb oxami de,
(R)- 1-b enzy1-3 -(3 -(difluoromethoxy)pheny1)-N-((S)-3-methyl-1,1 -di oxi
dotetrahy drothi ophen-3 -
y1)-4,5,6,7 -tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3 -(3-(difluoromethoxy)pheny1)-N-((S)-3 -methy1-1,1-di oxidotetrahy drothi
ophen-3 -y1)-1-
((tetrahy dro-2H-py ran-4-yl)methyl)-4,5 ,6,7-tetrahy dro-1H-indazol e-6-carb
oxami de,
(6R)-1-(1-cy anoethyl)-3-(5-(difluoromethoxy)-2-fluoropheny1)-N-(3 -methy1-1,1-
di oxi dothietan-
3 -y 0-4,5,6,7-tetrahy dro-1H-indazol e-6- carb oxami de,
(6R)-3-(5 -(difluoromethoxy)-2-fluoro pheny1)-N-(3 -methy1-1,1-di oxi dothi
etan-3 -y1)-1 -(1 -
(thi azol-2-yl)ethyl)-4,5,6,7-tetrahy dro -1H-indazol e-6-carb oxami de,
(R)- 1 -is opropyl-N-(3-methy1-1,1-di oxi dothi etan-3-y1)-3 -(3-(1-
(trifluoromethyl)cy cl opropyl)pheny1)-4,5,6,7-tetrahydro-1H-indazol e-6-
carboxami de,
(R)-3 -(3 -(1-cy anocy cl opropyl)pheny1)-1-is opropyl-N-(3 -methy1-1,1-di oxi
dothi etan-3-y1)-4,5,6,7-
tetrahy dro-1H-indazol e-6-carb oxami de,
(R)-3-(2-( 1,1-difluoroethyl)-5-fluoropyndin-4-y1)-1-isopropyl-/V-(4-methyl-
1,1-
di oxi dotetrahy dro-2H-thi opyran-4-y1)-4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de,
(R)- 1 -is opropyl-N-(3-methy1-1,1 -di oxi dothi etan-3-y1)-3 -(2-methy lbenzo
[di oxaz ol-4-y1)-4,5,6,7-
tetrahy dro-1H-ind azol e-6-carb oxami de,
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(R)-3 -(3 -(cy anomethyl)pheny1)-1-is opropyl-N-(3 -methy1-1,1-di oxidothietan-
3-y1)-4,5,6,7-
tetrahy dro-1H-indazole-6-carb oxamide,
(R)-3 -(5 -(tert-butylcarb amoyl)pyridin-3-y1)-1-isopropyl-N-(3-methyl- 1,1-
dioxidothietan-3 -y1)-
4,5,6,7-tetrahy dro-1H-indazole-6-carb oxamide,
(R)-3-(3-(cyanomethoxy)pheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-3-
y1)-4,5,6,7-
tetrahydro-IH-indazole-6-carboxamide,
(R)-3 -(3 -(1H-pyrazol-1-yl)pheny1)-1-is opropyl-N-(3 -methy1-1,1-
dioxidothietan-3-y1)-4,5,6,7-
tetrahy dro-1H-indazole-6-carb oxamide,
(R)-1-i s opropyl-N-(3-methy1-1,1-dioxidothietan-3-y1)-3 -(3-(methyl
sulfonyl)pheny1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3-(N-ethylsulfamoyl)pheny1)-1-isopropyl-N-(3 -methy1-1,1-
dioxidothietan-3-y1)-4,5,6,7-
tetrahy dro-1H-indazole-6-carb oxamide,
(R)-3 -(5 -ethyl -2-fl uoroph eny1)-1-i sopropyl-N-(3-methyl-1,1-di ox dothi
etan -3 -y1)-4,5,6,7-
tetrahy dro-1H-indazole-6-carb oxamide,
(R)-3 -(5 -cy an o-2-fl uoroph eny1)-1-i s opropy -N-(3 -m ethyl -1,1 -di oxi
dothi etan-3-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxamide,
(R)-3 -(3 -(1,1-difluoro ethy 1)pheny1)-1-isopropyl-N-(3-methyl- 1,1-
dioxidothietan-3-y1)-4,5,6,7-
tetrahy dro-1H-indazole-6-carb oxamide,
(R)-N-(3,3-difluoro-1-methylcy clobuty1)-3-(3-(1-hydroxycyclobutyl)pheny1)-1-
isopropyl-
4,5,6,7-tetrahydro-1H-indazole-6-carboxamide,
(R)-3-(3-(difluoromethoxy)ph eny1)-1-isopropyl-N-(3-methyl- 1,1-dioxidothi
etan-3
tetrahy dropyran o [4,3 -Cl py razole-6-carb oxamide,
(5)-3-(3-(difl uoromethoxy)pheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-
3-y1)-1,4,6,7-
tetrahy dropyran o [4,3-c] py razole-6-carb oxamide,
(R)-3 -(difluoromethoxy)-2-fluoropheny1)-1-is opropyl-N-(3-methy1-1,1-
dioxidothietan-3 -y1)-
1,4,6,7-tetrahy dropy rano [4,3 -c] pyrazole-6-carb oxamide, or
(R)-3 -(5 -cy clopropy1-2-fluoropheny1)-1-isopropyl-N-(3-methyl-1, 1-dioxi
dothi etan-3-y1)-1,4,6,7-
tetrahy dropyran o [4,3 -Cl py razole-6-carb oxamide.
In Embodiment 75 of the invention, the compound of formula I, or a
pharmaceutically
acceptable salt thereof, is:
31
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*
CI CI CI F
Ob id 10 I NµP
" el I N\'N g 0, \,NI !H ri el
\µ1\1
N
0,2.,-fir.A., ,) 0 0i, 0 0 05,S,..õ 0
41
F F , F , F ,
= 0).....F
* ONi....F ' 70 \
,.. Ircer__ ).--F
4k, (D ).....r
F F F
- H Si \PI H ,1110 I N
o-dNIr N 411r el N) \I i NI I
µN F Oj It
1 01 "..õ.õ) 0
Cti' -sS 0 01
Ns1,114,õc77
F F F
* ).--F
F * C))--F * 0)_..E * 0)_..E
F F F
i H . IP I µ,I,I
A)ly =I r
cag µ,1=N HON H 00 1 µ jsi HO1 i'N
N/
FAerrr ti tri / ll F-70 "tor
F F
F F ' F F
* 0,?......F
* osr.-F F ffikkh, 0 F
2- )---F
F F F F
4H)rel Nµisiel Nµ'N rOyei N"'N H
003;seNõ,..., N
1 0 F /..... V __.tre 0 ?,-.-- ) 0 N
3,8
N o...sil 0 F/......1
0
- Cl F F
, 2 , ,
A a
1?- ).--F
* . F cy-C))..-F
F F
F
E Hyel Nrµ I , ,
1 i imellr.. I Nµ,N H I \N
0 N 5C 0 t? C.F5H IF 0 -
i\,, 0 0 % 0 0
N
F F , F F
, , ,
Rt.,
* 0 = vrF * NH, cA-1----)[ )---F
0 F
(Is) 0 OP N\P CI:XNH el \pi C1CANH OW µ,N E H
Ne N No, N N
6õNH 2
*I 0 0 0 0 oirer
0:-- /0
F , F , F F
--N
N * )F
E 11-,11 I µN 0\--. F
N =
F
H H I µ,N .0 I
ll'N
4
I j \I
rõ.....õ...Nyo T N
0,, 0 )--- 05s......., 0
a
F 0' , e 0
32
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1# 0).....F
F =NN = 0)......F * F
I 1111 F F
Isys......)xN
F ...=
10 I µ,N F
050 01 \ N
r_kN,rt, NI, `N
NH .51 .
4 y tsõ;õ___ , H
\ N .
1r
ie'Ll
0'
?
0 00V....} 0 ,,,)"."- ,S 0
O'g
LO/
--
F * Y-F F * )".-F F * C).rF
* 0`.r.F
F F
F F
t H 01 N,N .1101 I \,1\I H =1
\,1,1 H 01
N
\N
r_scõN lip , Ir.
0 ;== s 0 (.......õNy. N
r.-.....õõNy.=N
07,S.,....õ0, 0 )"-- 0 0 ..õ..
)----
(pcV i
e Cfl e
,
N
* * 0µ....... N .
H 1 \,N
H 0 I µ,N H 5, ",, . H
01 µ.1\1
N.,., N N'
4 y ,,,,,..... r_,.... NItss. N
0 / .'". 05S, 0 i N-... CPA 0
S 0
e e d''')
, ,
N N
Nµ ON,.......
CI
....-
µ4-.. Fl µF
H 01 µ,N1 H 1 \ N 1. j 1 \,N1 H
1 \ N
(....,...õNy. N r.,.,..Nsirs. N' r.....-",( N
U.S,..õ.. U )---- 0,_,__o )---- V-....e 0 )--- 0V,./ 0
c? o o o
N
.0LIN:r. \rF (FF::::.)---N/1 / µ C)\--CF,
F
0 11
( 1, F 1 :-
N
N H 1 µ,N
s..õõNliõ. N' Ny N
N.
rS 0
t -.
0=S,,, 0 )--"-' 0.1:, 1r )i_. 05C 0 ,,)----
0111
6' 0
,
N
N N al& 0 O___
F 11-1/. )--"F Fat"F
H .= I `,N ,1,4,0
Ir I
\i'l
. H 1 \ N .......H 1 \ N pieltõ N D
< g Di? N6C)
r. 1r ,)-- .1.,) ' I), 0 DD,(\---6,õ
D
D D D
Aj 0 1
D D .1 D
C!,' 0 0
,
F * )--.F F * )"...F
cp..µ1, 0, ID.D F
*
F F õ...
F
8Erly. 1 : jsi u
F 0)nD
dYSI F H 01 \j µl H I \..N
õ..........N.r. N F (....õN.y. N
(:)'; ).---( , 0,- 0 ...)----( (35P....' 0
)- . 0
---. 011 1 0 D
D D
0 F e F , 0
-
,
F 40 0)._F rzFx...).....N
/ \ \.....- N F F
(kilt.... Nµ,N
H 1 \ N H 1 =

\ N H
=1 \pi
r......,NT. q F N ,,, N,
)F N._ ,F
(......._...N.y. Ni
cr=p.¨/ v.. 0 )---*EF 9d 0 ¨I¨

, F ov... o ,)--
o o F d F 0 ,
,
(::CP: 4f* 0)...-,F ilk 0
F * 0 ,F =-= C)F F
F F F F
H 1110 1 N',N1 H 1 \ N
H .01 \,N
r.....õN .r.. N rs,õ,N.y. N' 4Edy.1 471,1µ'N1 ciõNsy
N
05S.õ...,, 0 .)---- 05S,õ.õ,, 0 r'Ls. ,...õ.$ 0 ,s 0
e 0' G71
, , " g ,
'
33
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F * ())---F
F F * )¨F F
F
ryll,rr, 0 I Nµ'N F
H 1 µ,N
n V_ _õ.
s, 0 0,--cl 0 /,...,1 401 µ
CiLN,..õ...:N,Tto.l. N
0.11
.J>\--....,4 ir )____ >-"NH \---4 0

0
F * )--E * 0)....F *
F F
H . \ _I=1
N)...... (N.(LL= 1 'N1.1
y F N
Cca.,.... 11. el \,N
N
Ifs- N
0 ----0
/\----
---- 4* F 0)_...F 41, 0)__F
021? F F F
HN == IP µ,N H 5i µ,N I.
= li s \,N
-Tr N HO¨i-Ny N '0 Irs )........
0 ./)---- 0
* 0).....F
cgrs1-- 0)......F * 0,..,....F
F /
F
H 111011 I N.N
Nisj-YNir N 111 , I \,N ¨, H
7.0-S 0
o,r) i o o-//
rirrs' )----'
N
0 0
n n m
= 0).....F
* F
(D).--F 0
F F 040<ils. 0 I Nµ,N
H 11101 I" N
H H 0 I µN
Cr'--'

N.. 0
oz,,S,,,i 0 .")."---- ..,,,,,, N.
0* % 8
,)--- 0
0'
* (3)..F = 0 * 10)....F
F F F
0 . g H 0 I µ,^1 0 , rj OI µ,N 0 1 v, 5i `pi
0-A0-NT
1___ ,A1r N---,ci 0A0- y N
or-
/11 * 0 * 0)___F
F F F
pi 0 /..., i õ\11
0,0-N-r N
lip, Ogij) A
0.4s, - 1r ..
0
0 LO
m
F * (:))-F F * ON......F
i
F F . Oy_ F = C7')--.F
F
F oo Irl le 1 µ,N c?Ilre 0 I \ N' N,_ j; = I
Nµ,N
O'Sµe y O ).............. 4 Is
.. .
2-,---s 0,P Nr )-- 0-õ . 0....a0
0 . ,
,
7
F CI 4. 4 4/# C)).E F
F F
5I Isi N', H 0 I \,N
A, NI sir 1).... H 0 I µ14
4N,Itso N'
====== 0 /1"--- ..S )---
01.8 04-I 0
0'11
0 , 0'8
7 0 7 7
34
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ir-
*
F F
= 0\.......
F N \ 0
ci 1 ...... )c...F
,C
cL30--1..... )...F
F F
H .011 F
N,N
NT N
H
0SN H )
C)04:0.N.11r NI, H I µN
C?µ 01.07 N
=q.. .---
1
,
C N
* r N F F
F 1 \
N * C N
Ili `,ni Fl I N N I N
N' SIN
% 0 N rõ,õ.... N Its, N= vk ' Y =
N
N
0=Sq, NH )---- =35õ,õ..,.. 0 ).-- . 5
On I 0 )----. 0='5NH ,..).--
e 0
-(N 0 C N i
r ,--1_
N \--- IN *0 = N , r,14.) * r
I N N ell N,N 1101 0 0,...,0. 1 \,N
el N,N
o Cole N. % 0.10 N 0, Qle N N
0 Aq, N H )'--- 0 = sq. NH )---- Of'SqN H )---- IA T
o=sq, NH )----
0 n
Vt4% F
NC
F
H F* *
F
100 I N,N 0 I "'NJ dilly* Nµ'N
9 16I µ N
, ckye N
H
% N
)--.--
0.NH /\-- 005..;.se..1...,..... "iip, N, Ckle
8 )---- cyr=Sq,NH ..)--= 01,R
, 0
HO
7 c ---\
i F>f-F-4; c_..-- ---F4 FirE
H , I N.N
- H i . I µµN H I N N
rµ r/svi__ H I NN
...N......,.. ,r
F F 4" ..csNir ;L_
µ'-'s 8 )-- cf= 0'
,
,
, 1 NN 0.,.....kF
N
dii
N y. 1 I\Iµ'N H I NA
H I N',N N so N=
)t r.,õ...,,Tro. N
0=,S.,õ. 0
, 01 , H OA OH
OH 0 , 7
N
F 1 NIN F 4* F F . '...F
F......
F F
, PI I N,N1 H I µ,N I µ N
rõ....õ. N Irtso N 41-'111 ' " 110 N. 'Frl y
51 NV.N
0:50 1 1)1+ 0

0 OH e OH ane
0 OH o'..11
0 OH
n , n
F F
,11110 I N.I\I N T
i N . N'
OH 04 OH 0-=TS Or ) s0---'S
Its :4.-
0 0 0I-
OH 0'I
OH
,
7 ' 7
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N F
/ N\ Ojc-F F i \ IDN"JC-FF alk,
0 F
N N F * 0).....F
F
III Hss. I µ , N I I Id e F
F
1j, )+ 111 s4- reyell NI\ 'NI * 5i
ciNINõ.õ,OH
0.4 OH OH 0.:., 0 trOH
1
0 0 A , 0
n n
n
F
* O F F * OF F * 0).....F F
) - F F
F F
r OH
1--SN Y. NI: ,OH H el µ,N
.._ .k.N.1õ. 1,... 0 ' NN: 14
i .. õI, 0
1 Cr 01 0 0 0-r 0 - t
olti ID
, o ,
* 0.,.....F
* Osr-F
F F b 0,r.F
F F b C))'--F
0
0 F F 1 H F
050 I µ), H I " N
e I "ni , 1 III 01 " 00N 0 N
,N 00::1 ' .
N = 01 õ*e... 0 N0.1
OF 101 , ,
0, 0,
F F
# c\r-F # C\r-F F * 0F F
F F F
0 0 0
H I µ N H I \ N H ON 0 F
vi.N., N. vi,N N. 4N
* Nr g ki ,,
I µ,N
2"
Ol'A 1 0 N
1 0 5-61 0 )---
e
,
F alp A
Mig
F 1i* )--F F
4". 0>,-F
F = 0

H 1 \ N
0
H 0 H I µ1,1
H I µ N N . N.
N. N õ, I µ,,,
N' ci,N.ir N.
4 0 ,>--
oy,> 0 F ff.- 0
)' Olt 0 ').---
O'A
0
ifik 0 ,
4111
F , r ' F 4k
F
1 H 1 \ N H 0 1 \ N
.N1r 5-- 4 N .,....e N'
On I 0,..p. 8
0 ,or
In Embodiment 76 of the invention, the compound of formula 1, or a
pharmaceutically
acceptable salt thereof, is:
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__N
*
F \
F
H I '',N1 H I N
H N
N N T.=
05S 0 0=S.õ..õ..- 0 Q9S.. 0
e
/ = 0\ F / = 0 F
F F
N s,
0
H I 04 OH N NtH
0 I N
H
OH
0 , or 0
The present invention includes the pharmaceutically acceptable salts of the
compounds
defined therein.
In one embodiment, the present invention is a composition comprising an
effective
amount of at least one compound of Formula I, or a pharmaceutically acceptable
salt thereof
The invention also provides a pharmaceutical composition comprising an
effective
amount of at least one compound of Formula I, or a pharmaceutically acceptable
salt thereof, and
a pharmaceutically acceptable carrier.
The invention also provides a pharmaceutical composition comprising an
effective
amount of at least one compound of Formula 1, or a pharmaceutically acceptable
salt thereof, and
an effective amount of at least one other pharmaceutically active ingredient
(such as, for
example, a chemotherapeutic agent).
The invention also provides a pharmaceutical composition comprising an
effective
amount of at least one compound of Formula I, or a pharmaceutically acceptable
salt thereof, and
an effective amount of at least one other pharmaceutically active ingredient
(such as, for
example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.
In one embodiment, the present invention provides a composition for treating
hepatic
steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes
mellitus, obesity,
hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline,
dementia, cardiorenal
diseases such as chronic kidney diseases or heart failure comprising an
acceptable carrier and a
compound of Formula I, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention provides a composition for treating
hepatic
steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes
mellitus, obesity,
hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline,
dementia, cardiorenal
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diseases such as chronic kidney diseases or heart failure, comprising a
compound of Formula I,
or a pharmaceutically acceptable salt thereof
In one embodiment, the present invention provides a composition for treating
hepatic
steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes
mellitus, obesity,
hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline,
dementia, cardiorenal
diseases such as chronic kidney diseases or heart failure, comprising a
compound of Formula I,
or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
In one embodiment, the present invention provides a method of treating hepatic
steatosis,
nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus,
obesity, hyperlipidemia,
hypercholesterolemia, atherosclerosis, cognitive decline, dementia,
cardiorenal diseases such as
chronic kidney diseases or heart failure in a subject in need of such
treatment, comprising
administering to said subject a therapeutically effective amount of at least
one compound of
Formula 1, or a pharmaceutically acceptable salt thereof.
In one embodiment, the present invention provides a method of treating hepatic
steatosis,
nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus,
obesity, hyperlipidemia,
hypercholesterolemia, atherosclerosis, cognitive decline, dementia,
cardiorenal diseases such as
chronic kidney diseases or heart failure in a patient in need thereof,
comprising administering to
said patient a therapeutically effective amount of at least one compound of
Formula I, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier.
The methods of the invention include the administration of a pharmaceutical
composition
comprising at least one compound of the invention, or a pharmaceutically
acceptable salt thereof,
and a pharmaceutically acceptable carrier.
In another embodiment, the present invention includes a method of treating
NASH and/or
fibrosis, comprising administering to a patient in need thereof a compound of
Formula I, or a
pharmaceutically acceptable salt thereof
In another embodiment, the present invention includes a method of treating
NASH and/or
fibrosis, comprising administering to a patient in need thereof a compound of
Formula I, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable
carrier.
In another embodiment, the present invention includes a method of treating
NASH and/or
fibrosis, comprising administering to a patient in need thereof a composition
comprising a
compound of Formula I, or a pharmaceutically acceptable salt thereof
In another embodiment, the present invention includes a method of treating
NASH and/or
fibrosis, comprising administering to a patient in need thereof a composition
comprising a
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compound of Formula I, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically
acceptable carrier.
In another embodiment, the present invention provides for the use of a
compound of
Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for
treating NASH and/or fibrosis,
In another embodiment, the present invention includes the use of a compound of
Formula
I, or a pharmaceutically acceptable salt thereof, for the preparation of a
medicament for the
treatment of NASH and/or fibrosis,
"Alkyl" means branched- and straight-chain saturated aliphatic hydrocarbon
groups
having the specified number of carbon atoms when noted. If no number is
specified, 1-6 carbon
atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups.
Examples of alkyl
groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec- and
tert-butyl, pentyl,
hexyl, octyl, nonyl, and the like. For example, the term "C1-6a1ky1" includes
all of "Ci,alkyl"
defined as follows, plus the linear or branched chain alkyl groups, including
all possible isomers,
having 5 or 6 carbon atoms. "C1-6a1ky1" means linear or branched chain alkyl
groups, including
all possible isomers, having 1, 2, 3, 4, 5 or 6 carbon atoms, and includes
each of the alkyl groups
within C1-6a1ky1 including each of the hexyl and pentyl isomers as well as n-,
iso-, sec- and tert-
butyl (butyl, i-butyl, s-butyl, t-butyl, collectively -C4alkyl"; Bu = butyl),
n- and i-propyl (propyl,
i-propyl, collectively "C3alk-y1"; Pr = propyl), ethyl (Et) and methyl (Me).
Commonly used
abbreviations for alkyl groups are used throughout the specification, e.g.
methyl may be
represented by conventional abbreviations including "Me" or CH3 or a symbol
that is an
extended bond as the terminal group, e.g.
, ethyl may be represented by "Et- or CH2CH3,
propyl may be represented by "Pr- or CH2CH2CH3, butyl may be represented by -
Bu" or
HN
and --`4"
CH2CH2CH2CH3, etc. For example, the structures have
equivalent meanings. C1-6 alkyl includes n-, iso, sec- and t-butyl, n- and
isopropyl, ethyl and
methyl. If no number is specified, 1-6 carbon atoms are intended for linear or
branched alkyl
groups.
"Cyclic amine" refers to a cyclic ring comprising one nitrogen atom.
"Alkoxy" refers to an alkyl group linked to oxygen. Examples of alkoxy groups
include
methoxy, ethoxy, propoxy and the like.
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"Aryl- refers to an aromatic monocyclic or multicyclic ring moiety comprising
6 to 14
ring carbon atoms. In one embodiment, an aryl group contains from about 6 to
10 ring carbon
atoms. Monocyclic aryl rings include, but are not limited to, phenyl.
Multicyclic rings include,
but are not limited to, naphthyl and bicyclic rings wherein phenyl is fused to
a C5-7cycloalkyl or
C5-7cyc10a1keny1 ring. Aryl groups may be optionally substituted with one or
more substituents
as defined herein. Bonding can be through any of the carbon atoms of any ring.
"Fused Aryl" refers to an aryl ring fused with heterocyclyl or cycloalkyl.
"Halogen" or "Halo" includes fluorine, chlorine, bromine and iodine.
"Cycloalkyr refers to a non-aromatic mono-or multicyclic ring system
comprising about
3 to 10 ring carbon atoms. If no number of atoms is specified, 3-10 carbon
atoms are intended.
Cycloalkyl may also be fused, forming 1-3 carbocyclic rings. Non-limiting
examples of
monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl,
and cyclooctyl. The term Ci-6cycloalkyl" refers to a cycloalkyl group having 1
to 6 ring carbon
atoms. The term C3-6cyc10a1ky1" refers to a cycloalkyl group having 3 to 6
ring carbon atoms.
Thus, for example, "C3_6 cycloalkyl" includes each of cyclopropyl, cyclobutyl,
cyclopentyl, and
cyclohexyl. A cycloalkyl group is unsubstituted or substituted with one or
more ring system
substituents which may be the same or different, and are as defined within.
When cycloalkyl is a
substituent on an alkyl group, the cycloalkyl substituent can be bonded to any
available carbon in
the alkyl group. The following are illustrations of -C3_6cycloa1kyl
substituents on an alkyl group
1
0 0
wherein the substituent is cyclopropyl in bold:
"Haloalkyr refers to an alkyl group as defined within, wherein one or more of
the alkyl
group's hydrogen atoms has been replaced with a halogen. In one embodiment, a
haloalkyl
group has from 1 to 6 carbon atoms. Non-limiting examples of haloalkyl groups
include CH2F,
CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2C1 and CC13. The term "Ci-
6haloalkyl"
or "haloCi-6a1ky1"refers to a haloalkyl group having from 1 to 6 carbons.
"Haloalkoxy," "haloalkyl-O" and derivatives such as "halo(Ci-6)alkoxy" are
used
interchangeably and refer to halo substituted alkyl groups linked through the
oxygen atom.
Haloalkoxy include mono- substituted as well as multiple halo substituted
alkoxy groups. For
example, trifluoromethoxy, chloromethoxy, and bromomethoxy are included as
well as
OCH2CF3, OCH2CHF2, OCF2CF3, and OCF2CHF2.
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"Heterocyclyl," "heterocycle" or "heterocyclic" refers to monocyclic ring
structures in
which one or more atoms in the ring, the heteroatom(s), is an element other
than carbon.
Heteroatoms are typically 0, S or N atoms. A heterocycle containing more than
one heteroatom
may contain different heteroatoms. Bicyclic ring moieties include fused,
spirocyclic and bridged
bicyclic rings and may comprise one or more heteroatoms in either of the
rings. The ring
attached to the remainder of the molecule may or may not contain a heteroatom.
Either ring of a
bicyclic heterocycle may be saturated, partially unsaturated or unsaturated.
The heterocycle may
be attached to the rest of the molecule via a ring carbon atom, a ring oxygen
atom or a ring
nitrogen atom. Examples of heterocyclyl groups include: piperidine,
piperazine, morpholine,
pyrrolidine, tetrahydrofuran, azetidine, oxirane, or aziridine, and the like.
"Bicyclic heterocyclyl," "bicyclic heterocycle" or "bicyclic heterocyclic"
refers to a
heterocyclic ring fused to another ring system. The fusion may be bridged or
unbridged.
Except where noted, the term "heteroaryl", as used herein, represents a stable

monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein
at least one ring is
aromatic and contains from 1 to 4 heteroatoms selected from the group
consisting of 0, N and S.
Heteroaryl groups within the scope of this definition include but are not
limited to:
benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl,

benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl,
imidazolyl, indolinyl,
indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl,
isothiazolyl, isoxazolyl,
naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl,
pyrazinyl, pyrazolyl,
pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl,
quinolyl, quinoxalinyl,
tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,
dihydrobenzoimidazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,
dihydroindolyl,
dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl,
quinolinyl,
isoquinolinyl, oxazolyl, and tetra-hydroquinoline.
"Fused heteroaryl" is heteroaryl fused with an aryl or heteroaryl.
"Oxo" means an oxygen linked to an atom by a double bond. An example of an oxo
group is a doubly bonded oxygen in a ketone, sulfoxide, sulfone and sulfate.
-Hydroxyalkyl" or --hydroxy(C1_3)alliy1" means an alkyl group having one or
more
hydrogen atoms replaced by hydroxyl (-OH) groups
"Cyanoalkyr means an alkyl group having one or more hydrogen atoms replaced by
cyano (-CN) groups.
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"Hydroxyhaloalkyl- means an alkyl group having one or more hydrogen atoms
replaced
by hydroxyl (-OH) groups, and one or more hydrogen atoms replaced by a
halogen.
"Hydroxycycloalkyl" means a cyclic alkyl group having one or more hydrogen
atoms
replaced by hydroxyl (-OH) groups.
The term "composition" is intended to encompass a product comprising the
specified
ingredients in the specified amounts, as well as any product which results,
directly or indirectly,
from combination of the specified ingredients in the specified amounts.
The term "at least one" means one or more than one. The meaning of "at least
one" with
reference to the number of compounds of the invention is independent of the
meaning with
reference to the number of chemotherapeutic agents.
The term "chemotherapeutic agent" means a drug (medicament or pharmaceutically

active ingredient) for treating cancer (i.e., an antineoplastic agent).
The term "effective amount" means a "therapeutically effective amount". The
term
"therapeutically effective amount" means that amount of active compound or
pharmaceutical
agent that elicits the biological or medicinal response in a tissue, system,
animal or human that is
being sought by a researcher, veterinarian, medical doctor or other clinician.
The term "treating cancer" or "treatment of cancer" refers to administration
to a
mammal afflicted with a cancerous condition and refers to an effect that
alleviates the cancerous
condition by killing the cancerous cells, and also refers to an effect that
results in the inhibition
of growth and/or metastasis of the cancer.
Except where noted herein, the term "carbocycle" (and variations thereof such
as
"carbocyclic" or "carbocycly1") as used herein, unless otherwise indicated,
refers to a C3 to C6
monocyclic ring, e.g., C3-6 monocyclic carbocycle. The carbocycle may be
attached to the rest of
the molecule at any carbon atom which results in a stable compound. Saturated
carbocyclic rings
include, for example, "cycloalkyl" rings, e.g., cyclopropyl, cyclobutyl, etc.
Unsaturated
carbocyclic rings include, for example
A "stable" compound is a compound which can be prepared and isolated and whose

structure and properties remain or can be caused to remain essentially
unchanged for a period of
time sufficient to allow use of the compound for the purposes described herein
(e.g., therapeutic
or prophylactic administration to a subject).
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The compounds of the present disclosure are limited to stable compounds
embraced by
Formula I and its embodiments. For example, certain moieties as defined in
Formula I, may be
unsubstituted or substituted, and the latter is intended to encompass
substitution patterns (i.e.,
number and kind of substituents) that are chemically possible for the moiety
and that result in a
stable compound.
The term "substituted" means that one or more hydrogens on the designated atom
is
replaced with a selected from the indicated group, provided that the
designated atom's normal
valency under the existing circumstances is not exceeded, and that the
substitution results in a
stable compound. Where multiple substituent moieties are disclosed or claimed,
the substituted
compound can be independently substituted by one or more of the disclosed or
claimed
substituent moieties, singly or plurally. By independently substituted, it is
meant that the (two or
more) substituents can be the same or different. Combinations of substituents
and/or variables
are permissible only if such combinations result in stable compounds. If a
substituent is itself
substituted with more than one group, it is understood that these multiple
groups may be on the
same carbon or on different carbons, so long as a stable structure result. By
optionally
substituted, it is meant that compounds containing the specified optional
substituent(s) as well as
compounds that do not contain the optional substituent(s).
The wavy line '11 '1, as used herein, indicates a point of attachment to the
rest of the
compound.
Where ring atoms are represented by variables such as "X", e.g., , the
variables are
defined by indicating the atom located at the variable ring position without
depicting the ring
bonds associated with the atom. For example, when X in the above ring is
nitrogen, the
definition will show "N" and will not depict the bonds associated with it,
e.g., will not show
"=N-". Likewise, when X is a carbon atom that is substituted with bromide, the
definition will
show -C-Br" and will not depict the bonds associated with it, e.g., will not
show
"¨C-Br "
The invention also includes derivatives of the compound of Formula I, acting
as prodrugs
and solvates. Any pharmaceutically acceptable pro-drug modification of a
compound of the
invention which results in conversion in vivo to a compound within the scope
of the invention is
also within the scope of the invention. Prodrugs, following administration to
the patient, are
converted in the body by normal metabolic or chemical processes, such as
through hydrolysis in
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the blood, to the compound of Formula I. Such prodrugs include those that
demonstrate
enhanced bioavailability, tissue specificity, and/or cellular delivery, to
improve drug absorption
of the compound of I. The effect of such prodrugs may result from modification
of
physicochemical properties such as lipophilicity, molecular weight, charge,
and other
physicochemical properties that determine the permeation properties of the
drug.
For example, esters can optionally be made by esterification of an available
carboxylic
acid group or by formation of an ester on an available hydroxy group in a
compound. Similarly,
labile amides can be made. Pharmaceutically acceptable esters or amides of the
compounds of
the invention may be prepared to act as pro-drugs which can be hydrolyzed back
to an acid (or -
C00- depending on the pH of the fluid or tissue where conversion takes place)
or hydroxy form
particularly in vivo and as such are encompassed within the scope of the
invention. Included are
those esters and acyl groups known in the art for modifying the solubility or
hydrolysis
characteristics for use as sustained-release or prodrug formulations. Examples
of
pharmaceutically acceptable pro-drug modifications include, but are not
limited to, -C1-6alkyl
esters and ¨C1-6a1ky1 substituted with phenyl esters.
"Celiteg" (Fluka) diatomite is diatomaceous earth, and can be referred to as
"celite".
When any variable (e.g., 121 etc.) occurs more than one time in any
constituent or in
Formula 1 or other generic Formula herein, its definition on each occurrence
is independent of its
definition at every other occurrence. Combinations of substituents and/or
variables are
permissible only if such combinations result in stable compounds. In choosing
compounds of the
present invention, one of ordinary skill in the art will recognize that the
various substituents, i.e.
R1 etc., are to be chosen in conformity with well-known principles of chemical
structure
connectivity and stability. Unless expressly stated to the contrary,
substitution by a named
substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring,
or a saturated
heterocyclic ring) provided such ring substitution is chemically allowed and
results in a stable
compound.
It should be noted that, if a discrepancy between the chemical name and
structure exists,
the structure is understood to dominate.
Compounds of structural Formula I may contain one or more asymmetric centers
and can
thus occur as racemates and racemic mixtures, single enantiomers,
diastereoisomeric mixtures
and individual diastereoisomers. Centers of asymmetry that are present in the
compounds of
Formula I can all independently of one another have S configuration or R
configuration. When
bonds to the chiral carbon are depicted as straight lines in the structural
Formulas of the
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invention, it is understood that both the (R) and (S) configurations of the
chiral carbon, and
hence both enantiomers and mixtures thereof, are embraced within the Formulas.
Similarly,
when a compound name is recited without a chiral designation for a chiral
carbon, it is
understood that both the (R) and (S) configurations of the chiral carbon, and
hence individual
enantiomers and mixtures thereof, are embraced by the name. The production of
specific
stereoisomers or mixtures thereof may be identified in the Examples where such
stereoisomers or
mixtures were obtained, but this in no way limits the inclusion of all
stereoisomers and mixtures
thereof from being within the scope of the invention.
The compounds of this invention include all possible enantiomers and
diastereomers and
mixtures of two or more stereoisomers, for example mixtures of enantiomers
and/or
diastereomers, in all ratios. Thus, enantiomers are a subject of the invention
in enantiomerically
pure form, both as levorotatory and as dextrorotatory antipodes, in the form
of racemates and in
the form of mixtures of the two enantiomers in all ratios. In the case of a
cis/trans isomerism the
invention includes both the cis form and the trans form as well as mixtures of
these forms in all
ratios. The present invention is meant to comprehend all such stereo-isomeric
forms of the
compounds of structural Formula 1.
Compounds of structural Formula I may be separated into their individual
diastereoisomers by, for example, fractional crystallization from a suitable
solvent, for example
Me0H or Et0Ac or a mixture thereof, or via chiral chromatography using an
optically active
stationary phase. Optionally a derivatization can be carried out before a
separation of
stereoisomers. The separation of a mixture of stereoisomers can be carried out
at an intermediate
step during the synthesis of a compound of Formula I, or it can be done on a
final racemic
product. Absolute stereochemistry may be determined by X-ray crystallography
of crystalline
products or crystalline intermediates which are derivatized, if necessary,
with a reagent
containing an asymmetric center of known absolute configuration.
Alternatively, any
stereoisomer or isomers of a compound of Formula I may be obtained by
stereospecific synthesis
using optically pure starting materials or reagents of known absolute
configuration. The present
invention includes all such isomers, as well as salts, solvates (including
hydrates) and solvated
salts of such racemates, enantiomers, diastereomers and tautomers and mixtures
thereof
If desired, racemic mixtures of the compounds may be separated so that the
individual
enantiomers are isolated. The separation can be carried out by methods well
known in the art,
such as the coupling of a racemic mixture of compounds to an enantiomerically
pure compound
to form a diastereomeric mixture, followed by separation of the individual
diastereoisomers by
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standard methods, such as fractional crystallization or chromatography. The
coupling reaction is
often the formation of salts using an enantiomerically pure acid or base. The
diasteromeric
derivatives may then be converted to the pure enantiomers by cleavage of the
added chiral
residue. The racemic mixture of the compounds can also be separated directly
by
chromatographic methods utilizing chiral stationary phases, which methods are
well known in
the art.
For compounds of Formula I described herein which contain olefinic double
bonds,
unless specified otherwise, they are meant to include both E and Z geometric
isomers.
Some of the compounds described herein may exist as tautomers which have
different
points of attachment of hydrogen accompanied by one or more double bond
shifts. For example,
a ketone and its enol form are keto-enol tautomers. The individual tautomers
as well as mixtures
thereof are encompassed with compounds of Formula I of the present invention.
In the compounds of structural Formula 1, the atoms may exhibit their natural
isotopic
abundances, or one or more of the atoms may be artificially enriched in a
particular isotope
having the same atomic number, but an atomic mass or mass number different
from the atomic
mass or mass number predominately found in nature. The present invention as
described and
claimed herein is meant to include all suitable isotopic variations of the
compounds of structural
Formula I, and embodiments thereof For example, different isotopic forms of
hydrogen (H)
include protium ('H) and deuterium (2H, also denoted herein as D). Protium is
the predominant
hydrogen isotope found in nature. Enriching for deuterium may afford certain
therapeutic
advantages, such as increasing in vivo half-life or reducing dosage
requirements, or may provide
a compound useful as a standard for characterization of biological samples.
Isotopically-enriched
compounds within structural Formula I, can be prepared without undue
experimentation by
conventional techniques well known to those skilled in the art or by processes
analogous to those
described in the Schemes and Examples herein using appropriate isotopically-
enriched reagents
and/or intermediates.
It will be understood that the compounds of structural Formula I, may be
prepared as
pharmaceutically acceptable salts or as salts that are not pharmaceutically
acceptable when they
are used as precursors to the free compounds or their pharmaceutically
acceptable salts or in
other synthetic manipulations. The compounds of the present invention,
including the
compounds of the Examples, may also include all salts of the compounds of
Formula I, which,
owing to low physiological compatibility, are not directly suitable for use in
pharmaceuticals but
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which can be used, for example, as intermediates for chemical reactions or for
the preparation of
physiologically acceptable salts.
The compounds of the present invention may be administered in the form of a
pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt"
refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids including
inorganic or
organic bases and inorganic or organic acids.
Salts of basic compounds encompassed within the term "pharmaceutically
acceptable
salt" refer to non-toxic salts of the compounds of this invention which are
generally prepared by
reacting the free base with a suitable organic or inorganic acid.
Representative salts of basic
compounds of the present invention include, but are not limited to, the
following: acetate,
ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
borate, bromide,
butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride,
clavulanate, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,
malate, maleate, mandelate,
mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate,
mucate, napsy late,
nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),
palmitate,
pantothenate, phosphate/diphosphate, polygalacturonate, propionate,
salicylate, stearate, sulfate,
subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate,
triethiodide, valerate and
the like. Furthermore, where the compounds of the invention carry an acidic
moiety, suitable
pharmaceutically acceptable salts thereof include, but are not limited to,
salts derived from
inorganic bases including aluminum, ammonium, calcium, copper, ferric,
ferrous, lithium,
magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. In one
embodiment,
the salts of acidic compounds are as follows, the ammonium, calcium,
magnesium, potassium,
and sodium salts.
With basic reagents such as hydroxides, carbonates, hydrogencarbonates,
alkoxides and
ammonia, organic bases or alternatively basic amino acids the compounds of the
Formula I, form
stable alkali metal, alkaline earth metal or optionally substituted ammonium
salts.
Salts derived from pharmaceutically acceptable organic non-toxic bases include
salts of
primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines
and basic ion-
exchange resins, such as arginine, betaine, caffeine, choline, N,N-
dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine,
N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
hydrabamine,
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isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine,
polyamine resins,
procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine,
tromethamine,
and the like. Also, included are the basic nitrogen-containing groups may be
quatemized with
such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl
chloride, bromides
and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl
sulfates, long chain
halides such as decyl, lauryl, myristyl and steatyl chlorides, bromides and
iodides, aralkyl
halides like benzyl and phenethyl bromides and others.
The preparation of pharmacologically acceptable salts from compounds of the
Formula I,
capable of salt formation, including their stereoisomeric forms is carried out
known methods, for
example, by mixing a compound of the present invention with an equivalent
amount and a
solution containing a desired acid, base, or the like, and then collecting the
desired salt by
filtering the salt or distilling off the solvent. The compounds of the present
invention and salts
thereof may form solvates with a solvent such as water, ethanol, or glycerol.
The compounds of
the present invention may form an acid addition salt and a salt with a base at
the same time
according to the type of substituent of the side chain.
If the compounds of Formula 1, simultaneously contain acidic and basic groups
in the
molecule the invention also includes, in addition to the salt forms mentioned,
inner salts or
betaines (zwitterions). Salts can be obtained from the compounds of Formula I,
by customary
methods which are known to the person skilled in the art, for example by
combination with an
organic or inorganic acid or base in a solvent or dispersant, or by anion
exchange or cation
exchange from other salts.
The present invention includes compounds of structural Formula I, as well as
salts
thereof, particularly pharmaceutically acceptable salts, solvates of such
compounds and solvated
salt forms thereof, where such forms are possible unless specified otherwise.
Furthermore, compounds of the present invention may exist in amorphous form
and/or
one or more crystalline forms, and as such all amorphous and crystalline forms
and mixtures
thereof of the compounds of Formula I, including the Examples, are intended to
be included
within the scope of the present invention. In addition, some of the compounds
of the instant
invention may form solvates with water (i.e., a hydrate) or common organic
solvents such as but
not limited to Et0Ac. Such solvates and hydrates, particularly the
pharmaceutically acceptable
solvates and hydrates, of the instant compounds are likewise encompassed
within the scope of
this invention, along with un-solvated and anhydrous forms.
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Accordingly, the compounds within the generic structural formulas, embodiments
and
specific compounds described in the Examples and claimed herein encompass
salts, all possible
stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline
forms), solvate and
hydrate forms thereof and any combination of these forms, as well as the
salts, pro-drug forms
thereof, and salts of pro-drug forms thereof, where such forms are possible
unless specified
otherwise,
The invention also relates to medicaments containing at least one compound of
the
Formula I, and/or of a pharmaceutically acceptable salt of the compound of the
Formula I and/or
an optionally stereoisomeric form of the compound of the Formula I, or a
pharmaceutically
acceptable salt of the stereoisomeric form of the compound of Formula I,
together with a
pharmaceutically acceptable vehicle, carrier, additive and/or other active
substances and
auxiliaries.
The medicaments according to the invention can be administered by oral,
inhalative,
rectal or transdermal administration or by subcutaneous, intraarticular,
intraperitoneal or
intravenous injection. Oral administration is preferred. Coating of stents
with compounds of the
Formula I and other surfaces which come into contact with blood in the body is
possible.
The invention also relates to a process for the production of a medicament,
which
comprises bringing at least one compound of the Formula I into a suitable
administration form
using a pharmaceutically acceptable carrier and optionally further suitable
active substances,
additives or auxiliaries.
The present invention also relates to processes for the preparation of the
compounds of
Formula I which are described in the following and by which the compounds of
the invention are
obtainable.
The terms "therapeutically effective (or efficacious ) amount" and similar
descriptions
such as "an amount efficacious for treatment" are intended to mean that amount
of a
pharmaceutical drug that will alleviate the symptoms of the disorder,
condition or disease being
treated (i.e., disorder, condition or disease associated with DGAT2 activity)
in an animal or
human. The terms "prophylactically effective (or efficacious) amount" and
similar descriptions
such as "an amount efficacious for prevention" are intended to mean that
amount of a
pharmaceutical drug that will prevent or reduce the symptoms or occurrence of
the disorder,
condition or disease being treated (i.e., disorder, condition or disease
associated with DGAT2
activity) in an animal or human. The dosage regimen utilizing a compound of
the instant
invention is selected in accordance with a variety of factors including type,
species, age, weight,
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sex and medical condition of the patient; the severity of the condition to be
treated; the potency
of the compound chosen to be administered; the route of administration; and
the renal and
hepatic function of the patient. A consideration of these factors is well
within the purview of the
ordinarily skilled clinician for the purpose of determining the
therapeutically effective or
prophylactically effective dosage amount needed to prevent, counter, or arrest
the progress of the
condition. It is understood that a specific daily dosage amount can
simultaneously be both a
therapeutically effective amount, e.g., for treatment of hepatic steatosis,
diabetes mellitus,
obesity, hyperlipidemia, hypercholesterolemia, and a prophylactically
effective amount, e.g., for
treatment of NASH.
Disorders, conditions and diseases which can be treated or prevented by
inhibiting
DGAT2 by using the compounds of Formula I are, for example, diseases such as
non-alcoholic
steatohepatitis (NASH), fibrosis, hyperlipidemia, type I diabetes, type II
diabetes mellitus,
cognitive decline, dementia, coronary heart disease, ischemic stroke,
restenosis, peripheral
vascular disease, intermittent claudication, myocardial infarction,
dyslipidemia, post-prandial
lipemia, obesity, osteoporosis, hypertension, congestive heart failure, left
ventricular
hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic
nephropathy,
glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic
syndrome, syndrome X,
coronary heart disease, angina pectoris, thrombosis, atherosclerosis,
myocardial infarction,
transient ischemic attacks, stroke, hyperglycemia, hyperinsulinemia,
hypertriglyceridemia,
hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile
dysfunction, skin
and connective tissue disorders, hyper-apo B lipoproteinemia, non-alcoholic
fatty liver disease,
cardiorenal diseases such as chronic kidney diseases and heart failure, and
related diseases and
conditions.
The compounds of Formula I and their pharmaceutically acceptable salts can be
administered to animals, preferably to mammals, and in particular to humans,
as pharmaceuticals
by themselves, in mixtures with one another or in the form of pharmaceutical
preparations. The
term "patient" includes animals, preferably mammals and especially humans, who
use the instant
active agents for the prevention or treatment of a medical condition.
Administering of the drug to
the patient includes both self-administration and administration to the
patient by another person.
The patient may need, or desire, treatment for an existing disease or medical
condition, or may
be in need of or desire prophylactic treatment to prevent or reduce the risk
of occurrence of said
disease or medical condition. As used herein, a patient "in need" of treatment
of an existing
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condition or of prophylactic treatment encompasses both a determination of
need by a medical
professional as well as the desire of a patient for such treatment.
Furthermore, a subject of the present invention are pharmaceutical
preparations (or
pharmaceutical compositions) which comprise as active component a
therapeutically effective
dose of at least one compound of Formula I and/or a pharmaceutically
acceptable salt thereof and
a customary pharmaceutically acceptable carrier, i.e., one or more
pharmaceutically acceptable
carrier substances and/or additives.
Thus, a subject of the invention is, for example, said compound and its
pharmaceutically
acceptable salts for use as a pharmaceutical, pharmaceutical preparations
which comprise as
active component a therapeutically effective dose of said compound and/or a
pharmaceutically
acceptable salt thereof and a customary pharmaceutically acceptable carrier,
and the uses of said
compound and/or a pharmaceutically acceptable salt thereof in the therapy or
prophylaxis of the
above mentioned syndromes as well as their use for preparing medicaments for
these purposes.
The pharmaceuticals according to the invention can be administered orally, for
example
in the form of pills, tablets, lacquered tablets, sugar-coated tablets,
granules, hard and soft gelatin
capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or
suspensions, or rectally, for
example in the form of suppositories. Administration can also be carried out
parenterally, for
example subcutaneously, intramuscularly or intravenously in the form of
solutions for injection
or infusion. Other suitable administration forms are, for example,
percutaneous or topical
administration, for example in the form of ointments, tinctures, sprays or
transdermal therapeutic
systems, or the inhalative administration in the form of nasal sprays or
aerosol mixtures, or, for
example, microcapsules, implants or rods. The preferred administration form
depends, for
example, on the disease to be treated and on its severity.
For the production of pills, tablets, sugar-coated tablets and hard gelatin
capsules it is
possible to use, for example, lactose, starch, for example maize starch, or
starch derivatives, talc,
stearic acid or its salts, etc. Carriers for soft gelatin capsules and
suppositories are, for example,
fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc.
Suitable carriers for the
preparation of solutions, for example of solutions for injection, or of
emulsions or syrups are, for
example, water, physiologically sodium chloride solution, alcohols such as
ethanol, glycerol,
polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is
also possible to
lyophilize the compounds of Formula I and their pharmaceutically acceptable
salts and to use the
resulting lyophilisates, for example, for preparing preparations for injection
or infusion. Suitable
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carriers for microcapsules, implants or rods are, for example, copolymers of
glycolic acid and
lactic acid.
Suitable solid or galenical preparation forms are, for example, granules,
powders, coated
tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions,
emulsions, drops or
injectable solutions and preparations having prolonged release of active
substance, in whose
preparation customary excipients such as vehicles, disintegrants, binders,
coating agents,
swelling agents, glidants or lubricants, flavorings, sweeteners and
solubilizers are used.
Frequently used auxiliaries which may be mentioned are magnesium carbonate,
titanium dioxide,
lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose
and its derivatives,
animal and plant oils such as cod liver oil, sunflower, peanut or sesame oil,
polyethylene glycol
and solvents such as, for example, sterile water and mono- or polyhydric
alcohols such as
glycerol.
Besides the active compounds and carriers, the pharmaceutical preparations can
also
contain customary additives, for example fillers, disintegrants, binders,
lubricants, wetting
agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners,
colorants, flavorings,
aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers,
agents for achieving a
depot effect, salts for altering the osmotic pressure, coating agents or
antioxidants.
The dosage of the active compound of Formula I and/or of a pharmaceutically
acceptable
salt thereof to be administered depends on the individual case and is, as is
customary, to be
adapted to the individual circumstances to achieve an optimum effect. Thus, it
depends on the
nature and the severity of the disorder, condition or disease to be treated,
and also on the sex,
age, weight and individual responsiveness of the human or animal to be
treated, on the efficacy
and duration of action of the compounds used, on whether the therapy is acute
or chronic or
prophylactic, or on whether other active compounds are administered in
addition to compounds
of Formula I.
Combination Agents
The compounds of the present invention can be administered alone or in
combination
with one or more additional therapeutic agents disclosed herein or other
suitable agents,
depending on the condition being treated. Hence, in some embodiments the one
or more
compounds of the invention will be co-administered with other agents as
described above. When
used in combination therapy, the compounds described herein are administered
with the second
agent simultaneously or separately. This administration in combination can
include simultaneous
administration of the two agents in the same dosage form, simultaneous
administration in
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separate dosage forms, and separate administration. That is, a compound of
Formula (I) and any
of the agents described above can be formulated together in the same dosage
form and
administered simultaneously. Alternatively, a compound of Formula (I) and any
of the agents
described above can be simultaneously administered, wherein both the agents
are present in
separate formulations. In another alternative, a compound of Formula (I) can
be administered
just followed by and any of the agents described above, or vice versa. In some
embodiments of
the separate administration protocol, a compound of Formula (I) and any of the
agents described
above are administered a few minutes apart, or a few hours apart, or a few
days apart.
As one aspect of the present invention contemplates the treatment of the
disease/conditions with a combination of pharmaceutically active compounds
that may be
administered separately, the invention further relates to combining separate
pharmaceutical
compositions in kit form. The kit comprises two separate pharmaceutical
compositions: a
compound of Formula (1), and a second pharmaceutical compound. The kit
comprises a
container for containing the separate compositions such as a divided bottle or
a divided foil
packet. Additional examples of containers include syringes, boxes, and bags.
In some
embodiments, the kit comprises directions for the use of the separate
components. The kit form
is particularly advantageous when the separate components are preferably
administered in
different dosage forms (e.g., oral, parenteral; IV, transdermal and
subcutaneous), are
administered at different dosage intervals, or when titration of the
individual components of the
combination is desired by the prescribing health care professional.
One or more additional pharmacologically active agents may be administered in
combination with a compound of Formula I. An additional active agent (or
agents) is intended to
mean a pharmaceutically active agent (or agents) that is active in the body,
including pro-drugs
that convert to pharmaceutically active form after administration, which are
different from the
compound of Formula I and also includes free-acid, free-base and
pharmaceutically acceptable
salts of said additional active agents. Generally, any suitable additional
active agent or agents,
including but not limited to anti-hypertensive agents, anti-obetic, anti-
inflammatory, anti-
fibrotic, and anti-atherosclerotic agents such as a lipid modifying compound,
anti-diabetic agents
and/or anti-obesity agents may be used in any combination with the compound of
Formula 1 in a
single dosage formulation (a fixed dose drug combination), or may be
administered to the patient
in one or more separate dosage formulations which allows for concurrent or
sequential
administration of the active agents (co-administration of the separate active
agents).
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Examples of additional active agents which may be employed include but are not
limited
to angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril,
captopril, ceronapril,
cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril,
lisinopril, moveltipril, perindopril,
quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II
receptor antagonists
(e.g., losartan i.e., COZAAR valsartan, candesartan, olmesartan,
telmesartan and any of these
drugs used in combination with hydrochlorothiazide such as HYZAAR CR));
neutral
endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone
antagonists,
aldosterone synthase inhibitors, renin inhibitors (e.g. urea derivatives of di-
and tri-peptides,
amino acids and derivatives, amino acid chains linked by non-peptidic bonds,
di- and tri-peptide
derivatives, peptidyl amino diols and peptidyl beta-aminoacyl aminodiol
carbamates; also, and
small molecule renin inhibitors including diol sulfonamides and, N-morpholino
derivatives, N-
heterocyclic alcohols and pyrolimidazolones; also, pepstatin derivatives and
fluoro- and chloro-
derivatives of statone-containing peptides, enalkrein, RO 42-5892, A 65317, CP
80794, ES
1005, ES 8891, SQ 34017, aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoy1-2-
methylpropy1)-5-
amino-4-hydroxy-2,7-diisopropy1-8-14-methoxy-3-(3-methoxypropoxy)-phenyll-
octanamid
hemifumarate) SPP600, SPP630 and SPP635), endothelin receptor antagonists,
phosphodiesterase-5 inhibitors (e.g. sildenafil, tadalfil and vardenafil),
vasodilators, calcium
channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem,
gallopamil, niludipine,
nimodipins, nicardipine), potassium channel activators (e.g., nicorandil,
pinacidil, cromakalim,
minoxidil, aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide),
sympatholitics, beta-
adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol,
carvedilol, metoprolol, or
metoprolol tartate), alpha adrenergic blocking drugs (e.g., doxazosin,
prazosin or alpha
methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.g.
hydralazine); lipid
lowering agents e.g., HMG-CoA reductase inhibitors such as simvastatin and
lovastatin which
are marketed as ZOCOR and MEVACOR in lactone pro-drug form and function as
inhibitors
after administration, and pharmaceutically acceptable salts of dihydroxy open
ring acid HMG-
CoA reductase inhibitors such as atorvastatin (particularly the calcium salt
sold in LIPITORk),
rosuvastatin (particularly the calcium salt sold in CRESTORCW), pravastatin
(particularly the
sodium salt sold in PRAVACHOLO), fluvastatin (particularly the sodium salt
sold in
LESCOLCO, cerivastatin, and pitavastatin; a cholesterol absorption inhibitor
such as ezetimibe
(ZETIA/k) and ezetimibe in combination with any other lipid lowering agents
such as the HMG-
CoA reductase inhibitors noted above and particularly with simvastatin
(VYTORINIt) or with
atorvastatin calcium; niacin in immediate-release or controlled release forms,
and/or with an
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HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and
acifran, as well as
niacin receptor partial agonists; anti-cholesterol agents such as PCSK9
inhibitors (alirocumab,
evolocumab), NexletolTm (bempedoic acid, ACL inhibitor), and Vascepak
(Icosapent ethyl);
metabolic altering agents including insulin and insulin mimetics (e.g.,
insulin degludec, insulin
glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g.,
sitagliptin, alogliptin,
omarigliptin, linagliptin, vildagliptin); insulin sensitizers, including (i)
fl-klotho/FGFR1
activating monoclonal antibody (e.g. MK-3655), pan FGFR1-4/KLB modulators,
FGF19
analogue (e.g. Aldafermin) (ii) PPARy agonists, such as the glitazones (e.g.
pioglitazone, AMG
131, CHS 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone,
and
balaglitazone), and other PPAR ligands, including (1) PPARa/y dual agonists
(e.g.ZYH2, ZYH1,
GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and
naveglitazar); (2) PPARa
agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate,
ciprofibrate,
fenofibrate, bezafibrate), (3) selective PPARy modulators (SPPARyM's), (e.g.,
such as those
disclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409, WO
2004/020408, and WO 2004/066963); (4) PPARy partial agonists, (5) PPAR a/6
dual agonists
(e.g. Elafibranor ); (iii) biguanides, such as metformin and its
pharmaceutically acceptable salts,
in particular, metformin hydrochloride, and extended-release formulations
thereof, such as
GlumetzaTM, FortametTM, and GlucophageXRTM; and (iv) protein tyrosine
phosphatase-1B (PTP-
1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs
(e.g., insulin detemir,
insulin glulisine, insulin degludec, insulin glargine, insulin lispro and
inhalable formulations of
each); leptin and leptin derivatives and agonists; amylin and amylin analogs
(e.g., pramlintide);
sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide,
glyburide, glipizide,
glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide); a-
glucosidase inhibitors
(e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists (e.g.,
MK-3577, MK-
0893, LY-2409021 and KT6-971); incretin mimetics, such as GLP-1, GLP-1
analogs,
derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide,
semaglutide,
albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and
BIM-51077,
including intranasal, transdermal, and once-weekly formulations thereof), bile
acid sequestering
agents (e.g., colestilan, colestimide, col esevalam hydrochloride, col
estipol, cholestyramine, and
dialkylaminoalkyl derivatives of a cross-linked dextran), acyl CoA:cholesterol
acyltransferase
inhibitors, (e.g., avasimibe); antiobesity compounds; agents intended for use
in inflammatory
conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs,
glucocorticoids,
and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators
(GKAs) (e.g.,
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AZD6370); inhibitors of 11I3-hydroxysteroid dehydrogenase type 1, (e.g., such
as those disclosed
in U.S. Patent No. 6,730,690, and LY-2523199); CETP inhibitors (e.g.,
anacetrapib, torcetrapib,
and evacetrapib): inhibitors of fructose 1,6-bisphosphatase, (e.g., such as
those disclosed in U.S.
Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476);
inhibitors of acetyl
CoA carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated Protein Kinase (AMPK)
activators;
other agonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119
(e.g., MBX2982
and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., such as
those disclosed
in WO 2009/001836); neuromedin U receptor agonists (e.g., such as those
disclosed in WO
2009/042053, including, but not limited to, neuromedin S (NMS)); SCD
modulators (e.g.
Aramchol); GPR-105 antagonists (e.g., such as those disclosed in WO
2009/000087); SGLT
inhibitors (e.g., ASP1941, SGLT-3, SGLT-2 such as empagliflozin,
dapagliflozin, canagliflozin,
and ertugliflozin, BI-10773, remogloflozin, TS-071, tofogliflozin,
ipragliflozin, and LX-4211):
inhibitors of acyl coenzyme A carboxylase (ACC, MK-4074); inhibitors of
diacylglycerol
acyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid
synthase; inhibitors of
acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2);
agonists
of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR);
ileal
bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics,
and PACAP
receptor 3 agonists; IL-lb antibodies, (e.g., X0MA052 and canakinumab);, anti-
fibrotic and/or
anti-inflammatory agents (CCR2/CCR5 dual receptor antagonist (e.g.
cenicriviroc); galectin 3
inhibitor (e.g. belapectin, GB-1107, GB-1211), siRNA against HSP 47 (e.g. BMS-
986263);
NSAID derived from pirfenidone (e.g. hydronidone), A3AR agonist (e.g.
namodenoson,
FM101); TGFTX4 (e.g. nitazoxanide); 5-lipoxygenase inhibitor (e.g.
tipelukast), Bifunctional
urate inhibitor (e.g. ACQT1127), adiponectin receptor agonist (e.g. ALY688),
TNF receptor
antagonist (e.g. atrosimab), Autotaxin inhibitor (e.g. BLD-0409, TJC 0265, TJC
0316), CCL24
blocking monoclonal antibody (e.g. CM101), IL-11 inhibitor (e.g. ENx 108A),
LPA1 receptor
antagonist (e.g. EPGN 696), Dual JAK1/2 inhibitor (e.g. EX 76545), GPR
antagonist (e.g.
GPR91 antagonist), Integrin avI31, avI33 and avI36 inhibitor (e.g. IDL 2965),
NLRP3 antagonist
(e.g. IFM-514), inflammasome inhibitors (e.g. JT194, JT349), Cell membrane
permeability
inhibitor (e.g. Larazotide), CCR5 antagonist (e.g. Ieronlimab), 'TNF inhibitor
(e.g. LIVNate),
integrin avI36 inhibitor (e.g. MORF beta6), NLRP inflammasome antagonists,
siRNA (e.g. OLX
701), dual TFG13/Hedgehog inhibitor (e.g. Oxy 200), GPR40 agonist/GPR84
antagonist (e.g.
PBI-4547), neutrophil elastase inhibitor (e.g. PHP-303), integrin inhibitor
(e.g. PLN-1474),
TGFI31 modulator (e.g.PRM-151), CCK receptor antagonist (e.g. proglumide),
LOXL2 inhibitor
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(e.g. PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitor (e.g.
cGAS/STING
antagonists), kinase inhibiting RNase, membrane protein mAbs, tumor necrosis
factor inhibitor,
NRF2 activator (e.g. SCO 116), SSA inhibitor (e.g. TERN 201), TRAIL2 agonist
(e.g.
TLY012), IL-6 receptor antagonist (e.g. TZLS 501), A0C3 inhibitor (e.g. UD-
014),
SSAONAP-1 inhibitor, TREM2); anti-oxidant (e.g. vitamin E); anti-inflammatory
agents (e.g.
norfloxacin, ciprofloxacin, ceftriaxone); coagulation modifiers (e.g. anti-
coagulants, anti-platelet
agents, pentoxifylline, vitamin K, DDAVP); ; dual GIP and GLP-1 receptor
agonist (e.g.
tirzepetide); dual GLP-1/GRA (e.g. cotadutide, ALT-801, DD 01, G49, PB-718);
dual GLP-1
(e.g. CT 868); GLP-1/GRA/GIP triple agonist (e.g. HM15211); GRP120
stimulant/inflammasome modulator/PPARy dual agonist (e.g. KDT501); GLP-1/FGF21
(e.g.
YH25724); GLP-1 agonist (e.g. Ozempic (semaglutide sc), XW 003); selective
thyroid hormone
receptor-0 agonist (e.g. resmetirom); apoptosis modulators (JNK-1 inhibitor
(e.g. CC-90001),
Peroxidase inhibitor (e.g. AZM198), ASK-1 inhibitor (e.g. CS-17919, SRT 015));

erythropoietin-stimulating agents (erythropoietin receptor agonist (e.g.
cibinetide)); glucose
pathway modulators (SGLT-2 inhibitor (e.g. Forxiga, Farxiga (dapagliflozin));
dual SGLT-1/2
inhibitor (e.g. licogliflozin), Glucose-6-P dehydrogenase inhibitor (e.g.
fluasterone) LAPS
glucagon combo (e.g. HM14320), SGLT-1 inhibitor (e.g. SGL5213)); immune
modulators
(TLR4 inhibitor (e.g. GBK-233), immunomodulatory polyclonal antibody (e.g. IMM-
124E),
TLR4 antagonist (e.g. JKB-122), CD3 monoclonal antibody (e.g.foralumab), TLR4
antagonist
(e.g. JKB 133), TLR4 inhibitor (e.g. mosedipimod), Macrophage inhibitor via
CD206 targeting
(e.g. MT2002), TLR2/4 antagonist (e.g. VB-201, VB-703), immunomodulatory
polyclonal
antibody (e.g. IMM-124E)); incretin-based therapies (GLP-1 agonist (e.g.
Ozempic (semaglutide
sc), XW 003), GLP-I/glucagon dual receptor agonist (e.g. HM12525A), prandial
insulin (e.g.
ORMD 0801)); lipid modulators (AMPK Activator/ Glutathione transferase (e.g.
oltipraz),
'THR-beta agonist (e.g. resmetirom, VK2809, MGL-3745, ALG-009, ASC41, CNPT-
101101,
TERN 501), 1BAT inhibitor (e.g. elobixibat, CJ 14199), omega-6- fatty acid
(e.g. epeleuton),
FASN inhibitor (e.g. TVB2640, FT 4101, FT 8225), ANGPTL3 inhibitor (e.g.
vupanorsen),
PNPLA3 inhibitor (e.g. AZD2693), RAS domain kinase inhibitor (e.g. BioE1115),
NTCP
inhibitor (e.g. bulevirtide), P2Y13 receptor agonist (e.g. CER-209), omega-3
fatty acid,
HSD171313 inhibitor; metabolism modulators (FXR agonist (e.g. Ocaliva
(obeticholic acid),
10T022), recombinant variant of FGF19 (e.g. aldafermin), bi-specific FGFR1/KLB
antibody
(e.g. BFKB8488A), mTOT modulator (e.g. MSDC-0602K), pegylated analog of FGF21
(e.g.
pegbelfermin, BMS-986171), non-bile FXR agonist (e.g. cilofexor, EDP-305, EYP
001,
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tropifexor, MET409, AGN-242256, AGN-242266, EDP 297, HPG 1860, MET642, RDX023,

TERN 101), ACC inhibitor (e.g. firsocostat, PF-05221304), ketohexokinase
inhibitor (e.g. PF-
06835919), AMPK activator (e.g. PXL770, MSTM 101, 0304), bile acid modulator
(e.g.
Albiero), FGF21 analog (e.g. BI089-100), MOTSc analog (e.g. CB4211),
cyclophilin inhibitor
(e.g. CRV 431), FGF19 (e.g. DEL 30), mitochondrial uncoupler (e.g. GEN 3026),
FXR/GPCR
dual agonist (e.g. INT-767), Cvsteamine derivative (e.g. KB-GE-001), dual
amylin and
calcitonin receptor agonist (e.g. KBP-089), transient FXR agonist (e.g. M
1217), anti-beta-klotho
(KLB)-FGFR1c receptor complex mAb (e.g. MK3655), GDF15 analog (e.g. NGM395),
cyclophilin inhibitor (e.g. NV556), LXR modulator (e.g. PX 329, PX 655, PX
788), LXR inverse
agonist (e.g. PX016), deuterated obeticholic acid (e.g. ZG 5216)); PPAR
modulators (dual
PPARa/y agonist (e.g. elafibranor), PPAR pan agonist (e.g. lanifibranor),
PPARa agonists (e.g.
Parmodia), PPARy agonist (e.g. CHS 131), MPC inhibitor (e.g. PXL065), PPAR
.5/7 agonist
(e.g.T3D 959)); RAAS mIMModulators (mineralocorticoid receptor antagonist
(e.g.
apararenone, eplerenone, spironolactone), angiotensin receptor blocker (e.g.
losartan
potassium)); neurotransmitter modulators (cannabinoid receptor modulator, CB1
receptor
antagonist (e.g. CRB-4001, IM-102, nimacimab), TPH1 inhibitor (e.g. CU 02),
GPR120 agonist
(e.g. KBR2001), combination of cannabinoid and botanical anti-intlammatory
compound (e.g.
SCN 002)); PDE Modulator (PDE4 inhibitor (e.g. ART 648)); CYP2E1 inhibitor
(e.g. SNP-610);
cell therapies (e.g. HepaStem)and bromocriptine mesylate and rapid-release
formulations
thereof; or with other drugs beneficial for the prevention or the treatment of
the above-mentioned
diseases including nitroprusside and diazoxide the free-acid, free-base, and
pharmaceutically
acceptable salt forms of the above active agents where chemically possible.
The present invention includes the pharmaceutically acceptable salts of the
compounds
defined herein, including the pharmaceutically acceptable salts of all
structural formulas,
embodiments and classes defined herein. Reference to the compounds of
structural Formula (1)
includes the compounds of other generic structural Formulas, such as Formulas
and
embodiments that fall within the scope of Formula (I).
Dosages of the Compounds of Formula (I)
If the patient is responding, or is stable, after completion of the therapy
cycle, the therapy
cycle can be repeated according to the judgment of the skilled clinician. Upon
completion of the
therapy cycles, the patient can be continued on the compounds of the invention
at the same dose
that was administered in the treatment protocol. This maintenance dose can be
continued until
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the patient progresses or can no longer tolerate the dose (in which case the
dose can be reduced
and the patient can be continued on the reduced dose).
Those skilled in the art will recognize that the actual dosages and protocols
for
administration employed in the methods of the invention may be varied
according to the
judgment of the skilled clinician. The actual dosage employed may be varied
depending upon the
requirements of the patient and the severity of the condition being treated.
Determination of the
proper dosage for a particular situation is within the skill of the art. A
determination to vary the
dosages and protocols for administration may be made after the skilled
clinician considers such
factors as the patient's age, condition and size, as well as the severity of
the condition being
treated and the response of the patient to the treatment.
The dosage regimen utilizing a compound of the instant invention is selected
in
accordance with a variety of factors including type, species, age, weight, sex
and medical
condition of the patient; the severity of the condition to be treated; the
potency of the compound
chosen to be administered; the route of administration; and the renal and
hepatic function of the
patient. A consideration of these factors is well within the purview of the
ordinarily skilled
clinician for the purpose of determining the therapeutically effective or
prophylactically effective
dosage amount needed to prevent, counter, or arrest the progress of the
condition. It is
understood that a specific daily dosage amount can simultaneously be both a
therapeutically
effective amount, e.g., for treatment of an oncological condition, and a
prophylactically effective
amount, e.g., for prevention of an oncological condition.
While individual needs vary, determination of optimal ranges of effective
amounts of the
compound of the invention is within the skill of the art. For administration
to a human in the
curative or prophylactic treatment of the conditions and disorders identified
herein, for example,
typical dosages of the compounds of the present invention can be about 0.05
mg/kg/day to about
50 mg/kg/day, for example at least 0.05 mg/kg, at least 0.08 mg/kg, at least
0.1 mg/kg, at least
0.2 mg/kg, at least 0.3 mg/kg, at least 0.4 mg/kg, or at least 0.5 mg/kg, and
preferably 50 mg/kg
or less, 40 mg/kg or less, 30 mg/kg or less, 20 mg/kg or less, or 10 mg/kg or
less, which can be
about 2.5 mg/day (0.5 mg/kg x 5 kg) to about 5000 mg/day (50 mg/kg x 100 kg),
for example.
For example, dosages of the compounds can be about 0.1 mg/kg/day to about 50
mg/kg/day,
about 0.05 mg/kg/day to about 10 mg/kg/day, about 0.05 mg/kg/day to about 5
mg/kg/day, about
0.05 mg/kg/day to about 3 mg/kg/day, about 0.07 mg/kg/day to about 3
mg/kg/day, about 0.09
mg/kg/day to about 3 mg/kg/day, about 0.05 mg/kg/day to about 0.1 mg/kg/day,
about 0.1
mg/kg/day to about 1 mg/kg/day, about 1 mg/kg/day to about 10 mg/kg/day, about
1 mg/kg/day
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to about 5 mg/kg/day, about 1 mg/kg/day to about 3 mg/kg/day, about 3 mg/day
to about 500
mg/day, about 5 mg/day to about 250 mg/day, about 10 mg/day to about 100
mg/day, about 3
mg/day to about 10 mg/day, or about 100 mg/day to about 250 mg/day. Such doses
may be
administered in a single dose or may be divided into multiple doses.
Pharmaceutical Compositions
The compounds of Formula I and their pharmaceutically acceptable salts can be
administered to animals, preferably to mammals, and in particular to humans,
as pharmaceuticals
by themselves, in mixtures with one another or in the form of pharmaceutical
compositions. The
term "subject" or "patient" includes animals, preferably mammals and
especially humans, who
use the instant active agents for the prevention or treatment of a medical
condition.
Administering of the compound of Formula Ito the subject includes both self-
administration and administration to the patient by another person. The
subject may need, or
desire, treatment for an existing disease or medical condition, or may be in
need of or desire
prophylactic treatment to prevent or reduce the risk of occurrence of said
disease or medical
condition. As used herein, a subject "in need" of treatment of an existing
condition or of
prophylactic treatment encompasses both a determination of need by a medical
professional as
well as the desire of a patient for such treatment.
Methods for the safe and effective administration of most of these agents are
known to
those skilled in the art. In addition, their administration is described in
the standard literature.
If the patient is responding, or is stable, after completion of the therapy
cycle, the therapy
cycle can be repeated according to the judgment of the skilled clinician. Upon
completion of the
therapy cycles, the patient can be continued on the compounds of the invention
at the same dose
that was administered in the treatment protocol. This maintenance dose can be
continued until
the patient progresses or can no longer tolerate the dose (in which case the
dose can be reduced
and the patient can be continued on the reduced dose).
Those skilled in the art will recognize that the actual dosages and protocols
for
administration employed in the methods of the invention may be varied
according to the
judgment of the skilled clinician. The actual dosage employed may be varied
depending upon the
requirements of the patient and the severity of the condition being treated.
Determination of the
proper dosage for a particular situation is within the skill of the art. A
determination to vary the
dosages and protocols for administration may be made after the skilled
clinician takes into
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account such factors as the patient's age, condition and size, as well as the
severity of the
condition being treated and the response of the patient to the treatment.
The amount and frequency of administration of the compound of Formula I, and
any
additional agents will be regulated according to the judgment of the attending
clinician
(physician) considering such factors as age, condition and size of the patient
as well as severity
of the condition being treated.
The compounds of the invention are also useful in preparing a medicament that
is useful
in treating NASH and fibrosis.
The instant compounds are also useful in combination with therapeutic,
chemotherapeutic
and anti-cancer agents for the treatment of hepatic cellular carcinoma.
Combinations of the
presently disclosed compounds with therapeutic, chemotherapeutic and anti-
cancer agents are
within the scope of the invention. Examples of such agents can be found in
Cancer Principles
and Practice of Oncology by V.T. Devita and S. Hellman (editors), 9th edition
(May 16, 2011),
Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the
art would be able to
discern which combinations of agents would be useful based on the particular
characteristics of
the drugs and the cancer involved. Such agents include the following: estrogen
receptor
modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed
death-ligand 1 (PD-
L1) inhibitors, androgen receptor modulators, retinoid receptor modulators,
cytotoxic/cytostatic
agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-
CoA reductase
inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse
transcriptase
inhibitors, inhibitors of cell proliferation and survival signaling,
bisphosphonates, aromatase
inhibitors, siRNA therapeutics, y-secretase inhibitors, agents that interfere
with receptor tyrosine
kinases (RTKs) and agents that interfere with cell cycle checkpoints.
The chemotherapeutic agent can be administered according to therapeutic
protocols well
known in the art. It will be apparent to those skilled in the art that the
administration of the
chemotherapeutic agent can be varied depending on the cancer being treated and
the known
effects of the chemotherapeutic agent on that disease. Also, in accordance
with the knowledge of
the skilled clinician, the therapeutic protocols (e.g., dosage amounts and
times of administration)
can be varied in view of the observed effects of the administered therapeutic
agents on the
patient, and in view of the observed responses of the cancer to the
administered therapeutic
agents. The particular choice of chemotherapeutic agent will depend upon the
diagnosis of the
attending physicians and their judgment of the condition of the patient and
the appropriate
treatment protocol.
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The initial administration can be made according to established protocols
known in the
art, and then, based upon the observed effects, the dosage, modes of
administration and times of
administration can be modified by the skilled clinician.
The determination of the order of administration, and the number of
repetitions of
administration of the chemotherapeutic agent during a treatment protocol, is
well within the
knowledge of the skilled physician after evaluation of the condition being
treated and the
condition of the patient.
Thus, in accordance with experience and knowledge, the practicing physician
can modify
each protocol for the administration of a chemotherapeutic agent according to
the individual
patient's needs, as the treatment proceeds. All such modifications are within
the scope of the
present invention.
The agent can be administered according to therapeutic protocols well known in
the art. It
will be apparent to those skilled in the art that the administration of the
anti-cancer agent can be
varied depending on the cancer being treated and the known effects of the anti-
cancer agent on
that disease.
The initial administration can be made according to established protocols
known in the
art, and then, based upon the observed effects, the dosage, modes of
administration and times of
administration can be modified by the skilled clinician.
The particular choice of agent will depend upon the diagnosis of the attending
physicians
and their judgment of the condition of the patient and the appropriate
treatment protocol.
The determination of the order of administration, and the number of
repetitions of
administration of the agent during a treatment protocol, is well within the
knowledge of the
skilled physician after evaluation of the cancer being treated and the
condition of the patient.
Thus, in accordance with experience and knowledge, the practicing physician
can modify
each protocol for the administration of an anti-cancer agent according to the
individual patient's
needs, as the treatment proceeds. All such modifications are within the scope
of the present
invention.
The attending clinician, in judging whether treatment is effective at the
dosage
administered, will consider the general well-being of the patient as well as
more definite signs
such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor
growth, actual
shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be
measured by
standard methods such as radiological studies, e.g., CAT or MRI scan, and
successive
measurements can be used to judge whether or not growth of the tumor has been
retarded or even
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reversed. Relief of disease-related symptoms such as pain, and improvement in
overall condition
can also be used to help judge effectiveness of treatment.
The compounds, compositions and methods provided herein are useful for the
treatment
of cancer. Cancers that may be treated by the compounds, compositions and
methods disclosed
herein include, but are not limited to: Liver: hepatoma (hepatocellular
carcinoma),
cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma,
hemangioma.
PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab and
MPDL3280A.
PDL- inhibitors include atezolizumab, avelumab, and durvalumab.
The invention further relates to a method of treating hepatic cellular
carcinoma in a
human patient comprising administration of a compound of the invention (i.e.,
a compound of
Formula I) and a PD-1 antagonist to the patient. The compound of the invention
and the PD-1
antagonist may be administered concurrently or sequentially.
In particular embodiments, the PD-1 antagonist is an anti-PD-1 antibody, or
antigen
binding fragment thereof In alternative embodiments, the PD-1 antagonist is an
anti-PD-Li
antibody, or antigen binding fragment thereof In some embodiments, the PD-1
antagonist is
pembrolizumab (KEYTRUDATm, Merck & Co., Inc., Kenilworth, NJ, USA), nivolumab
(OPDIVOTM, Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab
(LIBTAY0Tm,
Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab
(TECENTRIQTm,
Genentech, San Francisco, CA, USA), durvalumab (IMFINZITm, AstraZeneca
Pharmaceuticals
LP, Wilmington, DE), or avelumab (BAVENCIOTM, Merck KGaA, Darmstadt, Germany).
In some embodiments, the PD-1 antagonist is pembrolizumab. In particular sub-
embodiments, the method comprises administering 200 mg of pembrolizumab to the
patient
about every three weeks. In other sub-embodiments, the method comprises
administering 400
mg of pembrolizumab to the patient about every six weeks.
In further sub-embodiments, the method comprises administering 2 mg/kg of
pembrolizumab to the patient about every three weeks. In particular sub-
embodiments, the
patient is a pediatric patient.
In some embodiments, the PD-1 antagonist is nivolumab. In particular sub-
embodiments,
the method comprises administering 240 mg of nivolumab to the patient about
every two weeks.
In other sub-embodiments, the method comprises administering 480 mg of
nivolumab to the
patient about every four weeks.
In some embodiments, the PD-1 antagonist is cemiplimab. In particular
embodiments, the
method comprises administering 350 mg of cemiplimab to the patient about every
3 weeks.
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In some embodiments, the PD-1 antagonist is atezolizumab. In particular sub-
embodiments, the method comprises administering 1200 mg of atezolizumab to the
patient about
every three weeks.
In some embodiments, the PD-1 antagonist is durvalumab. In particular sub-
embodiments, the method comprises administering 10 mg/kg of durvalumab to the
patient about
every two weeks.
In some embodiments, the PD-1 antagonist is avelumab. In particular sub-
embodiments,
the method comprises administering 800 mg of avelumab to the patient about
every two weeks.
A compound of the instant invention, or a pharmaceutically acceptable salt
thereof, may
also be useful for treating cancer in combination with the following
therapeutic agents:
pembrolizumab (Keytruda*), abarelix (Plenaxis depot*); aldesleukin (Prokine*);
Aldesleukin
(Proleukin*); Alemtuzumabb (Campath*); alitretinoin (Panretin*); allopurinol
(Zyloprim*);
altretamine (Hexalen0); amifostine (Ethyo10); anastrozole (Arimidex0); arsenic
trioxide
(Trisenox*); asparaginase (Elspar*); azacitidine (Vidaza*); bevacuzimab
(Avastin));
bexarotene capsules (Targretink); bexarotene gel (Targretin0); bleomycin
(Blenoxane0);
bortezomib (Velcadelk); busulfan intravenous (Busulfex*); busulfan oral
(Myleran(*);
calusterone (Methosarb*); capecitabine (Xeloda(*); carboplatin (Paraplatin*);
carmustine
(BCNU , BiCNU*)); carmustine (Gliadel ); carmustine with Polifeprosan 20
Implant (Gliadel
Wafer)); celecoxib (Celebrex*); cetuximab (Erbitux*); chlorambucil
(Leukeran*); cisplatin
(Platinol*); cladribine (Leustatin*, 2-CdA*); clofarabine (Clolar*);
cyclophosphamide
(Cytoxan , Neosar*); cyclophosphamide (Cytoxan Injection*); cyclophosphamide
(Cytoxan
Tablet ); cytarabine (Cytosar-U*); cytarabine liposomal (DepoCyt0);
dacarbazine (DTIC-
Dome*); dactinomycin, actinomycin D (Cosmegen*); Darbepoetin alfa (Aranesp*);
daunorubicin liposomal (DanuoXomek); daunorubicin, daunomycin (Daunorubicin*);
daunorubicin, daunomycin (Cerubidine*); Denileukin diftitox (Ontakik);
dexrazoxane
(Zinecard0); docetaxel (Taxotere0); doxorubicin (Adriamycin PFS0); doxorubicin

(Adnamycing, Rubexg); doxonibicin (Adriamycin PFS Injecti on ); doxonibicin
liposomal
(Doxilk); dromostanolone propionate (Dromostanoloneg); dromostanolone
propionate
(Masterone injection*); Elliott's B Solution (Elliott's B Solution*);
epirubicin (Ellence*);
Epoetin alfa (epogen*); erlotinib (Tarceva*); estramustine (Emcytk); etoposide
phosphate
(Etopophos0); etoposide, VP-16 (Vepesid0); exemestane (Aromasin0); Filgrastim
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(Neupogen0), floxuridine (intraarterial) (FUDRO); fludarabine (Fludarag);
fluorouracil, 5-FU
(Adrucilk); fulvestrant (Faslodexk); gefitinib (Iressak); gemcitabine
(Gemzark); gemtuzumab
ozogamicin (Mylotargg); goserelin acetate (Zoladex Implant ); goserelin
acetate (Zoladexg),
histrelin acetate (Histrelin implant ); hydroxyurea (Hydreag); Ibritumomab
Tiuxetan
(Zevaling); idarubicin (Idamycink); ifosfamide (IFEXk); imatinib mesylate
(Gleeveck);
interferon alfa 2a (Roferon Ag); Interferon alfa-2b (Intron Ag); irinotecan
(Camptosarg);
lenalidomide (Revlimid0); letrozole (Femarag); leucovorin (Wellcovorink,
Leucovorin0);
Leuprolide Acetate (Eligardk); levamisole (Ergamisolg); lomustine, CCNU
(CeeBUg);
meclorethamine, nitrogen mustard (Mustargeng); megestrol acetate (Megaceg);
melphalan, L-
PAM (Alkeran0); mercaptopurine, 6-MP (Purinethol0); mesna (Mesnex0); mesna
(Mesnex
tabs ); methotrexate (Methotrexateg); methoxsalen (Uvadexg); mitomycin C
(Mutamycing);
mitotane (Lysodreng); mitoxantrone (Novantroneg); nandrolone phenpropionate
(Durabolin-
50k); nelarabine (Arranonk); Nofetumomab (Verlumak); Oprelvekin (Neumegak);
oxaliplatin
(Eloxating); paclitaxel (Paxeneg); paclitaxel (Taxolg); paclitaxel protein-
bound particles
(Abraxane0); palifermin (Kepivance0); pamidronate (Arediak); pegademase
(Adagen
(Pegademase Bovine) ); pegaspargase (Oncasparg); Pegfilgrastim (Neulastag);
pemetrexed
disodium (Alimtag); pentostatin (Nipentg); pipobroman (Vercyteg); plicamycin,
mithramycin
(Mithracink); porfimer sodium (Photofring); procarbazine (Matulanek);
quinacrine
(Atabrineg); Rasburicase (Elitekg); Rituximab (Rituxank); Ridaforolimus;
sargramostim
(Leukine0); Sargramostim (Prokinek); sorafenib (Nexavark); streptozocin
(Zanosar0);
sunitinib maleate (Sutentk); talc (Sclerosolg); tamoxifen (Nolvadexk);
temozolomide
(Temodarg); teniposide, VM-26 (Vumong); testolactone (Teslack); thioguanine, 6-
TG
(Thioguanine0); thiotepa (Thioplexk); topotecan (Hycamtin0); toremifene
(Fareston0);
Tositumomab (Bexxarg); Tositumomab/I-131 tositumomab (Bexxarg); Trastuzumab
(Hercepting); tretinoin, ATRA (Vesanoidg); Uracil Mustard (Uracil Mustard
Capsules );
valrubicin (Valstark); vinblastine (Velbank); vincristine (Oncovink);
vinorelbine
(Navelbine0); vorinostat (Zolinzag) and zoledronate (Zometa0), or a
pharmaceutically
acceptable salt thereof
Methods for Making the Compounds of Present Invention
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The following examples are provided so that the invention might be more fully
understood. Unless otherwise indicated, the starting materials are
commercially available. They
should not be construed as limiting the invention in any way.
Several methods for preparing the compounds of this invention are described in
the
following Schemes and Examples. Starting materials and intermediates are
purchased, made
from known procedures, or as otherwise illustrated. Some frequently applied
routes to the
compounds of Formula I are also described by the Schemes as follows. In some
cases, the order
of carrying out the steps of reaction schemes may be varied to facilitate the
reaction or to avoid
unwanted reaction products. For stereoisomers, enantiomer A refers to the
faster/ earlier eluting
enantiomer and enantiomer B refers to the slower/ later eluting enantiomer at
the point of
separation and this nomenclature is maintained through the remainder of a
synthetic sequence for
a given enantiomeric series regardless of the possibility that subsequent
intermediates and final
compounds may have the same or opposite orders of elution.
List of Abbreviations:
ACN = acetonitrile
aq. = aqueous
= degrees Celcius
Cu(OAc)2 = copper acetate
DCM = dichloromethane
DEA = diethylamine
DIPEA = N,N-Diisopropylethylamine
DMAP = 4-(dimethylamino)pyridine
DMF = dimethylformamide
DPPA = Diphenylphosphoryl azide
dppf = 1,1'-bis(diphenylphosphino)ferrocene
Et0Ac = ethyl acetate
Et0H = ethanol
Et3N = triethylamine
FA = formic acid
Fe(acac)3 = ferric acetylacetonate
HATU = 14Bis(dirnethylarnino)methylene]-1 H4 ,2,3-triazolo[4,5-Npyri diniurn 3-
oxid-
hexafluorophosphate_ Hexafluorophosphate Azabenzotriazate 'retrainethyl
Uronium
h = hour(s)
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Hex = hexanes
iPrOH = isopropanol
KOAc = potassium acetate
Me = methyl
MeCN = acetonitrile
Me0H = methanol
MsCl= methanesulfonyl chloride
min = minutes
NIS = N-Iodosuccinimide
Pd(OAc)2 = palladium acetate
Pd2(dba)3 = tris(dibenylideneacetone)dipalladium (0)
rt or RT = room temperature
SFC = supercritical fluid chromatography
TFA = trifluoroacetic acid
'THF = tetrahydrofuran
TsCl= 4-methylbenzenesulfonyl chloride
TLC = thin layer chromatography
UV = ultraviolet
wt .% = percentage by weight
%w/v = percentage in weight of the former agent relative to the volume of the
latter agent
Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Zn(0Ac)2 = zinc acetate
LCMS conditions: column: ACQUITY UPLC-QDa BEH C18, 1.7mm, 2.1 x
50mm. Solvent system: A: Water 0.1% FA, B: ACN 0.1% FA
Gradient condition: 10-90% B, in 1.7 min, total run time 2.4 min
GENERAL SYNTHETIC SCHEMES
While the present invention has been described in conjunction with the
specific examples
set forth above, many alternatives, modifications and variations thereof will
be apparent to those
of ordinary skill in the art. In some cases, the order of carrying out the
steps of the reaction
schemes may be varied to facilitate the reaction or to avoid unwanted reaction
products. All such
alternatives, modifications and variations are intended to fall within the
spirit and scope of the
present invention.
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[General Scheme]
1,21
R2-X y.Xx4 114N I N I µ14
z ri .õ01 N: 'ijLz N:
0 0 0 R2
1-2 1-3
1-1
121 121
R3 NH
X
HOyL N' Ri I N
N z N'
0 0
R2
1-4
Compounds of formula I were prepared from 1-1 by C-C coupling with R1-boronic
acid or ester
to provide 1-2. N- substituted compounds (1-3) were prepared with R2-X via SN2
for alkyl
substituents or copper-mediated C-N coupling (Chan-Lam or Buchwald N-
arylation) for
aromatic substituents. Saponification of 1-3 provided the corresponding
carboxylic acid (1-4)
and subsequent amide coupling with the appropriate amines provided compounds
of formula I as
described by the general scheme. The order of steps for some examples may be
varied to
facilitate the syntheses.
INTERMEDIATES
Intermediate 1
2-(5-(difluoromethoxy)-2-fluoropheny1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane
1101 OH F 0 F
STEP A 110 STEP; 11101
F
Br Br
0 OINT-1
STEP A: 2-bromo-4-(difluoromethoxy)-1-fluorobenzene
At 0 C, to a stirred solution of 3-bromo-4-fluorophenol (10 g, 52.4 mmol),
KOH (8.81 g, 157
mmol), MeCN (52.4 ml), and water (52.4 ml) was added diethyl
(bromodifluoromethyDphosphonate (28.0 g, 105 mmol). The mixture was stirred at
rt for 1 h
then extracted three times with Et0Ac. The combined organic layers were washed
with water
and brine. The organic layer was then dried over MgSO4(s), filtered, and
concentrated in vacuo.
The crude product was purified by flash silica gel column chromatography (5%
Et0Ac in
hexanes) to afford the title compound. LC/MS = 241 [M+1].
STEP B: 2-(5-(difluoromethoxy)-2-fluoropheny1)-4,4.5.5-tetramethy1-1,3,2-
dioxaborolane
To a stirred solution of 2-bromo-4-(difluoromethoxy)-1-fluorobenzene (2 g,
8.30 mmol),
bis(pinacolato)diboron (2.53 g, 9.96 mmol), PdC12(dppf) (1.36 g, 1.66 mmol),
and dioxane (16.6
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ml) was added KOAc (2.44 g, 24.9 mmol). The mixture was stirred at 100 C for
16 h. After
cooling to rt, water was added and the aqueous layer was extracted three time
with Et0Ac. The
combined organic layers were washed with water and brine. The organic layer
was then dried
over MgSO4(s), filtered, and concentrated in vacuo. The crude product was
purified by flash
silica gel column chromatography (5% Et0Ac in hexanes) to afford the title
compound. LC/MS
= 289 [M+1].
By using procedures similar to those described in Intermediate 1 with
appropriate reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
Intermediate Structure Name LCMS [M-
F11
2 T' 2-(2-chloro-5- 305
CI
(difluoromethoxy)pheny1)-4,4,5,5-
14" tetramethy1-1,3,2-dioxaborolane
3 (1)-F 2-(5-
(difluoromethoxy)-2- 285
Me -4r"---
CT.Bs0 methylpheny1)-4,4,5,5-tetramethyl-
') 1,3,2-dioxaborolane
4 NJOF 5-
(difluoromethoxy)-2-methyl-3- 286
(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-yl)pyridine
5 Nir)õ.1; 0,F 2-
(difluoromethoxy)-5-fluoro-4- 290
F
(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-yl)pyridine
Intermediate 6
5-fluoro-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2-(2,2,2-
trifluoroethoxy)pyridine
F xkixt...1 0.,.CF,
STEFASTEP B
F
0.8.0 INT-6
STEP A: 5-fluoro-4-iodo-2-(2,2,2-trifluoroethoxy)pyridine
To a stirred solution of NaH (480 mg, 12 mmol) and DMSO (20 mL) was added
2,2,2-
trifluoroethan-1-ol (1.0 g, 10 mmol). The mixture was stirred at rt for 15
minutes then 2,5-
difluoro-4-iodopyridine (4.1 g, 17 mmol) was added. The mixture was stirred
for 2 h and water
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was added. The aqueous layer was extracted three times with Et0Ac. The
combined organic
layers were washed with water and brine. The organic layer was then dried over
MgSO4(s),
filtered, and concentrated in vacuo. The crude product was purified by flash
silica gel column
chromatography (10% Et0Ac in hexanes) to afford the title compound. LC/MS =
322 1M-F11.
STEP B: 5-fluoro-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2-(2,2,2-
trifluoroethoxy)pyridine
To a stirred solution of 5-fluoro-4-iodo-2-(2,2,2-trifluoroethoxy)pyridine
(1.06 g, 3.3 mmol),
bis(pinacolato)diboron (1.67 g, 6.6 mmol), PdC12(dppf) (242 mg, 0.33 mmol),
and dioxane (11
ml) was added KOAc (0.97 g, 9.9 mmol). The mixture was stirred at 100 C for
16 h. After
cooling to rt, water was added, and the aqueous layer was extracted three time
with Et0Ac. The
combined organic layers were washed with water and brine. The organic layer
was then dried
over MgSO4(s), filtered, and concentrated in vacuo. The crude product was
purified by flash
silica gel column chromatography (30% Et0Ac in hexanes) to afford the title
compound. LC/MS
= 322 1M+11.
By using procedures similar to those described in Intermediate 6 with
appropriate reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
Intermediate Structure Name LCMS
1M+11
7
FN 2-(2,2-difluoroethoxy)-5-fluoro-
304
4-(4,4,5,5-tetramethy1-1,3,2-
0,13,0
dioxaborolan-2-yl)pyridine
8 N 0
2-cyclopropoxy-5-fluoro-4- 280
(4,4,5,5-tetramethy1-1,3,2-
cr=B=0
dioxaborolan-2-yl)pyridine
Intermediate 9
5-(difluoromethoxy)-2-(difluoromethyl)-3-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-yOpyridine
me Ni?" TFSTEP A STEP BF STEP C F TF
Br Br F Br
INT-9
STEP A: 3-bromo-5-(difluoromethoxy)picolinaldehyde
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To a stirred solution of 3-bromo-5-(difluoromethoxy)-2-methylpyridine (1.27 g,
5.3 mmol) and
dioxane (11 mL) was added SeO2 (5.9 g, 53 mmol). The mixture was stirred at
140 C for 16 h.
After cooling to rt the mixture was filtered and concentrated in vacuo. The
crude product was
purified by flash silica gel column chromatography (20% Et0Ac in hexanes) to
afford the title
compound. LC/MS = 252 [M-F11.
STEP B: 3-bromo-5-(difluoromethoxy)-2-(difluoromethyl)pyridine
At 0 C, to a stirred solution of 3-bromo-5-(difluoromethoxy)picolinaldehyde
(1.14 g, 4.5 mmol)
and DCM (9 mL) was added (diethylamino)sulfur trifluoride (2.4 mL, 18.1 mmol).
The mixture
was stirred at rt for 1 h. Sat. aq. NaHCO3 was added and the aqueous layer was
extracted three
time with DCM. The combined organic layers were washed with water and brine.
The organic
layer was then dried over MgSO4(s), filtered, and concentrated in vacuo. The
crude product was
purified by flash silica gel column chromatography (10% Et0Ac in hexanes) to
afford the title
compound. LC/MS = 274 [M+11.
STEP C: 5-(difluoromethoxy)-2-(difluoromethyl)-3-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)pyri dine
To a stirred solution of 3-bromo-5-(difluoromethoxy)-2-
(difluoromethyl)pyridine (0.98 g, 3.6
mmol), bis(pinacolato)diboron (1.82 g, 7.2 mmol), PdC12(dppf) (263 mg, 0.36
mmol), and
dioxane (12 ml) was added KOAc (1.06 g, 10.8 mmol). The mixture was stirred at
100 C for 16
h. After cooling to rt, water was added and the aqueous layer was extracted
three times with
Et0Ac. The combined organic layers were washed with water and brine. The
organic layer was
then dried over MgSO4(s), filtered, and concentrated in vacuo. The crude
product was purified
by flash silica gel column chromatography (20% Et0Ac in hexanes) to afford the
title
compound. LC/MS = 322 [M+11.
Intermediate 10
5-fluoro-2-isopropoxy-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)pyridine
N OH N N
I 1,7õ." STEP A 1 STEP B 11T I
Br Br
0'13s0
...H... INT-10
STEP A: 4-bromo-5-fluoro-2-isopropoxypyridine
To a stirred solution of 4-bromo-5-fluoropyridin-2-ol (512 mg, 2.7 mmol) 2-
iodopropane (400
u.L, 4 mmol) and DCE (5.3 mL) was added Ag2CO3 (1.5 g, 5.3 mmol). The mixture
was stirred
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at rt for 16 h then filtered over Celite. The crude mixture was concentrated
in vacuo and the
crude product was used without further purification. LC/MS = 234 1M+11.
STEP B: 5-fluoro-2-isopropoxy-4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)pyridine
To a stirred solution of 4-bromo-5-fluoro-2-isopropoxypyridine (600 g, 2.6
mmol),
bis(pinacolato)diboron (1.3 g, 5.1 mmol), PdC12(dppf) (188 mg, 0.26 mmol), and
dioxane (8.5
ml) was added KOAc (755 mg, 7.7 mmol). The mixture was stirred at 100 C, for
16 h. After
cooling to rt, water was added and the aqueous layer was extracted three time
with Et0Ac. The
combined organic layers were washed with water and brine. The organic layer
was then dried
over MgSO4(s), filtered, and concentrated in vacuo. The crude product was
purified by flash
silica gel column chromatography (20% Et0Ac in hexanes) to afford the title
compound. LC/MS
= 282 1M+11.
Intermediate 11
2-(3-(2,2-difluoroethoxy)pheny1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane
so OH STEP; STEP B OJF
-11.-
INT-11
STEP A: 1-(2,2-difluoroethoxy)-3-iodobenzene
To a stirred solution of 3-iodophenol (1.0 g, 4.6 mmol), 2,2-difluoroethyl
trifluoromethanesulfonate (1.95 g, 9.1 mmol), and DMF (9 mL) was added Cs2CO3
(5.9 g, 18.2
mmol). The reaction mixture was heated to 60 C for 18 h. The reaction mixture
was cooled to rt
and water was added. The aqueous layer was extracted three times with Et0Ac.
The combined
organic layers were washed with water and brine. The organic layer was then
dried over MgSO4
(s), filtered, and concentrated in vacuo. The crude product was purified by
flash silica gel
column chromatography (10% Et0Ac in hexanes) to afford the title compound.
LC/MS = 285
1M+11.
STEP B: 2-(3-(2,2-difluoroethoxy)pheny1)-4,4,5,5-tetramethy1-1,3,2-
dioxaborolane
To a stirred solution of 1-(2,2-difluoroethoxy)-3-iodobenzene (500 mg, 1.76
mmol),
bis(pinacolato)diboron (671 mg, 2.64 mmol), Pd(dpp0C12 (258 mg, 0.35 mmol),
and dioxane
(5.8 mL) was added KOAc (691 mg, 7.04 mmol). The reaction mixture was heated
to 100 C for
21 h. The reaction mixture was cooled to rt and water was added. The aqueous
layer was
extracted three times with Et0Ac. The combined organic layers were washed with
water and
brine. The organic layer was then dried over MgSO4(s), filtered, and
concentrated in vacuo. The
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crude product was purified by flash silica gel column chromatography (10%
Et0Ac in hexanes)
to afford the title compound. LC/MS = 285 [M+11.
By using procedures similar to those described in Intermediate 11 with
appropriate reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
Intermediate Structure Name LCMS
[1\4+1[
12 Y 4-(difluoromethoxy)-2-(4,4,5,5- 272
Nr F F
0'9'0 tetramethy1-1,3,2-dioxaborolan-2-
yl)pyridine
13 9 3-(4,4,5,5-tetramethy1-1,3,2- 304
dioxaborolan-2-y1)-5-(2,2,2-
0-B-0
trifluoroethoxy)pyridine
14 q 3-(2,2-difluoroethoxy)-5-(4,4,5,5-
286
tetramethy1-1,3,2-dioxaborolan-2-
0,13,0
yl)pyridine
Intermediate 15
5-(difluoromethoxy)-2-methy1-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-
yl)pyridine
0 F
NH2 OH 0,F
N, STEP A NI STEP B STEP C T
F
0 0
Br Br Br
INT-15
STEP A: 5-bromo-6-methylpyridin-3-ol
To a mixture of 5-bromo-6-methylpyridin-3-amine (2 g, 10.69 mmol), HBF4 (10
ml, 10.69
mmol) and water (10 mL) was added sodium nitrite (0.812 g, 11.76 mmol) at 0 C.
The resulting
yellowish heterogeneous reaction mixture was stirred for 30 min at 0 C. After
addition of water
(5 mL), the mixture was heated to 100 C and stirred for 12 h. LCMS showed
that desired target
was formed. The mixture was poured into H20, then the mixture was extracted
with Et0Ac (x
3), the combined organic layers were washed with brine, dried over Na2SO4,
then filtered and
concentrated under reduced pressure. The residue was purified by column
chromatography on
silica (0-100% Et0Ac/hexanes) to afford the title compound (1.3 g). LC/MS =
188 and 190
[M+1].
STEP B: 3-bromo-5-(difluoromethoxy)-2-methylpyridine
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A 8 mL of tube was charged with 5-bromo-6-methylpyridin-3-ol (600 mg, 3.19
mmol), Cs2CO3
(3119 mg, 9.57 mmol) and DMF (4 mL) at 25 C. Then the mixture was bubble with

chlorodifluoromethane (2759 mg, 31.9 mmol), and the reaction was stirred at 60
C for 15 h.
LCMS showed that desired target was formed. The mixture was poured into H20,
then the
mixture was extracted with Et0Ac (x 3), the combined organic layers were
washed with brine,
dried over Na2SO4, then filtered and concentrated under reduced pressure. The
residue was
purified by column chromatography on silica (0-100% Et0Ac/hexanes) to afford
the title
compound. LC/MS = 238 and 240 [M+11.
STEP C: 5-(difluoromethoxy)-2-methy1-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-
2-y1)pyridine
A 8 mL of tube was charged with 3-bromo-5-(difluoromethoxy)-2-methylpyridine
(330 mg,
1.386 mmol), 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane) (528
mg, 2.080 mmol),
potassium acetate (408 mg, 4.16 mmol), PdC12(dppf) (101 mg, 0.139 mmol) and
1,4-Dioxane (3
mL) at 25 C. The mixture was bubbled with a stream of N2 for 2 min. The tube
was sealed and
heated to 80 C for 2 h. LCMS showed that desired target was formed. The
mixture was poured
into H20, then the mixture was extracted with Et0Ac (x 3). The combined
organic layers were
washed with brine, dried over Na2SO4, then filtered and concentrated under
reduced pressure.
The residue was purified by mass triggered reverse phase HPLC (ACN/water with
0.1% TFA
modifier) to afford the title compound. LC/MS = 204 [M+1] 45-(difluoromethoxy)-
2-
methylpyridin-3-yOboronic acid).
Intermediate 16
1,1-difluoropropan-2-y1 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate
o, F F
OH
STEP A
CF3
F F
F
INT-16
STEP A: 1,1-difluoropropan-2-y1 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate
At -78 'V, to a stirred solution of 1,1-difluoropropan-2-ol (1.8 mL, 20.8
mmol) and DCM (10.4
mL) was added Et3N (2.9 mL, 20.8 mmol) and nonfluorobutanesulfonyl fluoride
(4.9 mL, 27.1
mmol). The mixture was stirred at rt for 16 h then sat. aq. NaHCO3 was added.
The aqueous
layer was extracted three times with DCM. The organic layer was then dried
over MgSO4 (s),
filtered, and concentrated in vacuo. The crude product was used without
purification. LC/MS =
379 [M+1].
EXAMPLES
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The following experimental procedures detail the preparation of specific
examples of the instant
disclosure. The examples are for illustrative purposes only and are not
intended to limit the scope
of the instant disclosure in any way.
EXAMPLE 1
3 -(2-chloropheny1)-1-(4-fluoropheny1)-N-(3 -methy1-1,1-di oxi dotetrahy
drothiophen-3-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
ci CI
C
AylOnN STEP A STEP B Si ',NJ STEP ip,
STEP,D.
0
4Ik
CI
CI
HO Si \,N
STEP E 0.sH = I µN
N
0 0101--SN 0
Ex-1
STEP A: Methyl 3-iodo-4,5.6.7-tetrahydro-1H-indazole-6-carboxylate
To a round bottom flask was added methyl 4,5,6,7-tetrahydro-1H-indazole-6-
carboxylate (3.0 g,
16.7 mmol), NIS (5.6 g, 25.0 mmol), and DMF (33 mL). The reaction mixture was
stirred at 80
C for 30 mm. The reaction mixture was then cooled to rt and sat. NaHCO3 (aq)
was added. The
aqueous layer was extracted three times with Et0Ac. The combined organic
layers were washed
with sat. NaHCO3 (aq), water, and brine. The organic layer was then dried over
MgSO4(s),
filtered, and concentrated in vacuo. The crude product was purified by flash
silica gel column
chromatography (30% Et0Ac in hexanes) to afford the title compound. LC/MS =
307 [M+11.
STEP B: Methyl 3-(2-chloropheny1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate
To a stirred solution of methyl 3-iodo-4,5,6,7-tetrahydro-1H-indazole-6-
carboxylate (1.50 g,
4.90 mmol), (2-chlorophenyl)boronic acid (0.92 g, 5.88 mmol), Pd(dppf)C12
(0.36 g, 0.49
mmol), Na2CO3 (1.04 g, 9,80 mmol), and dioxane (12 mL) was added water (12
mL). The
reaction mixture was sparged with N2 for 5 mm at rt then heated to 100 C for
45 min. After
cooling to rt water was added. The aqueous layer was extracted three times
with Et0Ac. The
combined organic layers were washed with water and brine. The organic layer
was then dried
over MgSO4(s), filtered, and concentrated in vacuo. The crude product was
purified by flash
silica gel column chromatography (40% Et0Ac in hexanes) to afford the title
compound. LC/MS
=291 [M+1].
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STEP C: Methyl 3-(2-chloropheny1)-1-(4-fluoropheny1)-4,5,6,7-tetrahydro-1H-
indazole-6-
carboxylate
To a stirred solution of methyl 3-(2-chloropheny1)-4,5,6,7-tetrahydro-1H-
indazole-6-carboxylate
(600 mg, 2.06 mmol), Cu(OAc)2 (562 mg, 3.10 mmol), and (4-fluorophenyl)boronic
acid (577
mg, 4.13 mmol) in DCM (3.4 mL) was added pyridine (334 uL, 4.13 mmol). The
reaction
mixture was stirred open to air for 24 h. Water was added to the reaction
mixture and extracted
with DCM three times. The organic layer was then dried over MgSO4(s),
filtered, and
concentrated in vacuo. The crude product was purified by flash silica gel
column
chromatography (10% Et0Ac in hexanes) to afford the title compound. LC/MS =
385 1M+11.
STEP D: 3-(2-chloropheny1)-1-(4-fluoropheny1)-4,5,6,7-tetrahydro-1H-indazole-6-
carboxylic
acid
To a stirred solution of methyl 3-(2-chloropheny1)-1-(4-fluoropheny1)-4,5,6,7-
tetrahydro-IH-
indazole-6-carboxylate (467 mg, 1.21 mmol) in THF (2.6 mL) and Me0H (0.9 mL)
was added a
solution of NaOH (971 mg, 24.3 mmol) and water (2.6 mL). The reaction mixture
was heated to
60 C for 2 h. After cooling to rt the reaction mixture was acidified with
concentrated HC1 to pH
1. The reaction mixture was then extracted with Et0Ac three times. The
combined organic layers
with washed with brine, dried with MgSO4(s), filtered, and concentrated in
vacuo. The crude
product was used without purification. LC/MS = 371 1M+1].
STEP E: 3-(2-chloropheny1)-1-(4-fluoropheny1)-N-((S)-3-methyl-1,1-
dioxidotetrahydrothiophen-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
To a stirred solution of 3-(2-chloropheny1)-1-(4-fluoropheny1)-4,5,6,7-
tetrahydro-1H-indazole-6-
carboxylic acid (225 mg, 0.61 mmol) in DMF (3.0 mL) was added DIPEA (0.31 mL,
1.82
mmol), HATU (254 mg, 0.67 mmol), and (S)-3-amino-3-methyltetrahydrothiophene
1,1-dioxide
(100 mg, 0.67 mmol). The reaction mixture was stirred at rt for 16 h. The
mixture was filtered
and purified by mass triggered reverse phase HPLC (ACN/water with 0.1% FA
modifier) to
afford the title compound (Ex-1). LC/MS = 502 1M+11. DGAT2 IC50 (nm) =
37.9.The mixture of
two stereoisomers was purified by chiral preparative SFC (IC column, 20%
Me0H/CO2) to
afford Ex-la (faster eluting) and Ex-lb (slower eluting). Ex-lb: 1H NMR (600
MHz,
Chloroform-d) 6 7.56 - 7.49 (m, 2H), 7.46 (td, J = 5.7, 4.8, 2.9 Hz, 2H), 7.35
- 7.28 (m, 2H),
7.15 (t, = 8.5 Hz, 2H), 5.90 (d, .1=7.3 Hz, 1H), 3.60 (dd, .1 = 50.2, 13.8 Hz,
1H), 3.31 (dtd, .1 =
12.5, 8.3, 4.1 Hz, 1H), 3.20 (ddt, J= 12.3, 7.7, 3.6 Hz, 1H), 3.08 (dd, J =
16.0, 10.6 Hz, 1H),
3.03 (dd, J 13.8, 8.2 Hz, 1H), 2.88 - 2.74 (m, 2H), 2.65 - 2.57 (m, 2H), 2.52 -
2.41 (m, 1H),
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2.20 ¨ 2.11 (m, 1H), 2.08 (dd, J= 24.8, 10.2 Hz, 1H), 1.87 (ddd, J= 21.8,
12.4, 8.6 Hz, 1H),
1.60 (d, J = 2.8 Hz, 5H). LC/MS = 502 [M+1].
By using procedures similar to those described in Example 1 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
DGAT2
LCMS
Example Structure Name
ICso
[M+11
(nM)
(S)-3-(2-chloropheny1)-1-(4-
* fluoropheny1)-N-((S)-3-methy1-1,1-
ci
1101 dioxidotetrahydrothiophen-3-y1)-
la
502
3898
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (IC column, 20%
Me0H/CO2, faster eluting)
(R)-3-(2-chloropheny1)-1-(4-
fluoropheny1)-N-((5)-3-methyl-1,1-
1 b N H Nµ,N dioxidotetrahydrothiophen-3-y1)-
502
33.7
05,dr0 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (IC column, 20%
Me0H/C 02, faster eluting)
(R)-3-(3-(difluoromethoxy)pheny1)-1-
a& 0
(4-fluoropheny1)-N-((S)-3-methyl-
2 g H Si Nµp
1,1 -dioxidotetrahy drothiophen-3 -y1)- 534
0.63
N if
0 4,5,6,7-tetrahydro-1H-indazole-6-
F
carboxamide
(R)-3-(3-(difluoromethoxy)pheny1)-1-
c)) (5-fluoropyridin-2-y1)-N-((5)-3-
õ upp methyl-1,1-
3 535
4.9
03sr_e.õTr Nõ. rsµi
dioxidotetrahydrothiophen-3-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
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(R)-3-(3-(difluoromethoxy)pheny1)-1-
0Nr-F (5-fluoropy ridin-2-y1)-N-(3 -methyl-
4 drlyel N\'" 1,1-
dioxidothietan-3-y1)-4,5,6,7- 521 5.1
01 tetrahydro-1H-indazole-6-
F
carboxamide
1-(5-cyclopropy1-1,3,4-thiadiazol-2-
y1)-3-(5-(difluoromethoxy)pyridin-3-
y1)-N-((S)-3-methy1-1,1-
µ,K1
dioxidotetrahydrothiophen-3-y1)- 565
542.2
0:.0 0 rsil¨s
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (mixture of
diastereomers)
(6R)-3-(3-(difluoromethoxy)pheny1)-
1-(5-fluoropyridin-2-y1)-N-(3-
F methyltetrahydrofuran-3-y1)-4,5,6,7-
H
6a oCff tetrahydro-1H-indazole-6- 487
37.4
0
carboxamide (faster eluting with OD-
H column, 30% iPrOH (0.1%
DEA)/CO2)
(6R)-3-(3-(difluoromethoxy)pheny1)-
1-(5-fluoropyridin-2-y1)-N-(3-
methyltetrahydrofuran-3-y1)-4,5,6,7-
6b rEj rs,' tetrahydro-1H-indazole-6- 487
2.0
ir carboxamide (slower eluting with
OD-H column, 30% iPrOH (0.1%
DEA)/CO2)
(R)-N-(3,3-difluoro-1-
* Or methylcyclobuty1)-3-(3-
1. H
(difluoromethoxy)pheny1)-1-(5-
NN,N
7
F)r, N'it fluoropyridin-2-y1)-4,5,6,7-
507
12.0
tetrahydro-1H-indazole-6-
carboxamide
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(6R)-N-(3,3-difluoro-1-
(hydroxymethyl)cyclopenty1)-3-(3-
O F (difluoromethoxy)pheny1)-1-(5-
F;cyrei
8a fluoropyridin-2-y1)-4,5,6,7- 537
5.0
F 0
tetrahydro-1H-indazole-6-
F carboxamide (3rd eluting with AD-H
column, 35% Et0H/CO2)
(6R)-N-(3,3-difluoro-1-
(hydroxymethyDcyclopenty1)-3-(3-
*)_(difluoromethoxy)pheny1)-1-(5-
8b Ho...lily el N.,N
fluoropyridin-2-y1)-4,5,6,7- 537
35
F7/110 0 tetrahydro-1H-indazole-6-
F
carboxamide (4th eluting with AD-H
column, 35% Et0H/CO2)
(R)-3-(3-(difluoromethoxy)pheny1)-1-
= OSF (3,5-difluoropyridin-2-y1)-N-(3-

9 c..?1-01 Nµ'N methyl-1,1-dioxidothietan-3-y1)-
539 10.2
4,5,6,7-tetrahydro-1H-indazole-6-
F
carboxamide
1-(5-chloropyrimidin-2-y1)-3-(3-
(difluoromethoxy)pheny1)-N-(($)-3-
= )_F methyl-1,1-
ei \,N
dioxidotetrahydrothiophen-3-y1)- 552
37.02
oc-p 0 Nei--11
4,5,6,7-tetrahydro-1H-indazole-6-
oi
carboxamide (mixture of
diastereomers)
((R)-3-(5-(difluoromethoxy)-2-
F fluoropheny1)-1-(3,5-difluoropyridin-
2-y1)-N-(3-methy1-1,1-
11 4FNI-ireiN\'" 557
0.33
os" dioxidothietan-3-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-
carboxamide
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(R)-3-(5-(difluoromethoxy)pyridin-3-
1)1¨\ y1)- 1 -(5 -11 uoropy ri din-2 -y1)-N-
(3 ¨
H I .sp
12 005;0<.y. N meth 4-1 1-dioxidothietan-3- 1 -
522 65.8
) Y )
0 0 4,5,6,7-tetrahydro-1H-indazole-6-
F
carboxamide
(R)-3-(3-(3,3-
* = F, difluorocyclobutyl)pheny1)-1-(4-
fluoropheny1)-N-((5)-3-methyl-1,1-
13 H .10 558
20.0
N'ior dioxidotetrahydrothiophen-3-y1)-
F 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(5-(difluoromethoxy)pyridin-3-
y1)-1-(5-fluoropyridin-2-y1)-N-((S)-3-
methyl-1,1-
14 536
13.9
H I rj,r4
z
dioxidotetrahydrothiophen-3-y1)-
F 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(6R)-N-(3-cyanotetrahydrofuran-3-
y1)-3-(5-(difluoromethoxy)pyridin-3-
y1)-1-(5-fluoropyridin-2-y1)-4,5,6,7-
0 " I µ.NI
15a tetrahydro-1H-indazole-6- 499
17.4
carboxamide
(faster eluting with OD-H column,
30% iPrOH (0.1% DEA)/CO2)
(6R)-N-(3-cyanotetrahydrofuran-3-
\ y1)-3-(5-(difluoromethoxy)pyridin-3-
cF y1)-1-(5-fluoropyridin-2-y1)-4,5,6,7-
((xi...a... tetrahydro-1H-indazole-6- 499
236.4 15b
\ n
\ N
carboxamide
(slower eluting with OD-H column,
30% iPrOH (0.1% DEA)/CO2)
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3-(3-(difluoromethoxy)pheny1)-1-(5-
Nor F
fluoropyridin-2-y1)-N-((1R,2R)-2-
*
morpholino cy cl op enty1)-4,5,6,7-
16 00 I Nµ*" 556
66.9
tetrahydro- 1H-indazole-6-
60NH
carb oxami de
(mixture of diastereomers)
(R)-3-(3 -(1-
fik F fluoro cy cl opropyl)pheny1)-1-(4-
fluoropheny1)-N4S)-3-methyl-1,1-
17 21-DCNHiell Itrsi 526
70.7
di oxi dotetrahy drothi ophen-3 -y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de
(R)-3-(3 -(2-aminopropan-2-
fit NH.
yl)pheny1)-1-(4-fluoropheny1)-N-((S)-
9 1:yNH 01 1\4,N
3-methyl-1,1-
18 525
>10000
1r di oxi dotetrahy drothi ophen-3 -y1)-
4,5,6,7-tetrahy dro-1H-indazol e-6-
carb oxami de
(R)-3-(6-(difluoromethoxy)pyrazin-2-
y1)-1-(5-fluoropyridin-2-y1)-N-((5)-3-
= H I µN methyl-1,1-
19 N 1µ 537
>10000
di oxi dotetrahy drothi ophen-3 -y1)-
= H µNN
4di,5ox,
ddrroOt-h1:0p- ihnedna:30_1yei:- 3-
carb oxami de
(R) - 1-(5-fluoropy ri din-2-y1)-N-((5)-3-
20 - 4's methyl-1,1-
473
8434
or;sr_kõNr. N
(1-methyl-1H-pyrazol-5 -y1)-4,5,6,7-
tetrahydro- IH-indazol e-6-
carboxami de
EXAMPLE 21
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(R)-3-(2-(difluoromethoxy)-5-fluoropyridin-4-y1)-1-isopropyl-N-(4-methy1-1,1-
dioxidotetrahydro-2H-thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
F I F
/ = 0
CE4N STEP A F F F STEP B =Jµi STEP C
Itss"
0
F n)--F F /
µN STEP D
HOT y N
05.p,,, 0
0
EX-21
STEP A: (R)-3-(2-difluoromethoxy)-5-fluoropyridin-4-y1)4,5,6,7-tetrahydro-1H-
indazole-6-
carboxylate
To a stirred solution of (R)-methyl 3-iodo-4,5,6,7-tetrahydro-1H-indazole-6-
carboxylate (600
mg, 1.96 mmol), 2-(difluoromethoxy)-5-fluoro-4-(4,4,5,5-tetramethy1-1,3,2-
dioxaborolan-2-
yl)pyridine (567 mg, 1.96 mmol), Pd(dppf)C12 (287 mg, 0.39 mmol), Na2CO3 (623
mg, 5.88
mmol), and dioxane (3.2 mL) was added water (3.2 mL). The reaction mixture was
bubbled with
N2 for 5 minutes at rt then heated to 100 C for 15 minutes. After cooling to
rt water was added.
The aqueous layer was extracted three times with Et0Ac. The combined organic
layers were
washed with water and brine. The organic layer was then dried over MgSO4,
filtered, and
concentrated in vacuo. The crude product was purified by flash silica gel
column
chromatography (40% Et0Ac in hexanes) to afford the title compound. LC/MS =
342 [M+1].
STEP B: Methyl (R)-3-(2-(difluoromethoxy)-5-fluoropyridin-4-y1)-1-isopropy1-
4,5,6,7-
tetrahydro-1H-indazole-6-carboxylate
To a stirred solution of methyl (R)-3-(2-(difluoromethoxy)-5-fluoropyridin-4-
y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxylate (419 mg, 1.23 mmol), 2-iodopropane (417
mg, 2.46
mmol), and DMF (4.1 mL) was added cesium carbonate (1600 mg, 4.91 mmol). The
reaction
mixture was stirred at 100 C for 15 minutes. Water was added after cooling to
room
temperature. The aqueous layer was extracted three times with Et0Ac. The
combined organic
layers were washed with water and brine. The organic layer was then dried over
MgSO4(s),
filtered, and concentrated in vacuo. The crude product was purified by flash
silica gel column
chromatography (20% Et0Ac in hexanes) to afford the title compound. LC/MS =
384 [M+1].
STEP C: (R)-3-(2-(difluoromethoxy)-5-fluoropyridin-4-y1)-1-isopropy1-4,5,6,7-
tetrahydro-1H-
indazole-6-carboxylic acid
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To a stirred solution of methyl (R)-3-(2-(difluoromethoxy)-5-fluoropyridin-4-
y1)-1-isopropy1-
4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (306 mg, 0.80 mmol), LiOH (76 mg,
3.2 mmol),
THF (0.9 mL), and Me0H (0.9 mL) was added H20 (0.9 mL). After stirring at rt
for 10 min, the
reaction mixture was acidified with concentrated HC1 to pH 1. The reaction
mixture was then
extracted with Et0Ac three times. The combined organic layers with washed with
brine, dried
with MgSO4(s), filtered, and concentrated in vacuo. The crude product was used
without
purification. LC/MS = 370 [M+1].
STEP D: (R)-3-(2-(difluoromethoxy)-5-fluoropyridin-4-y1)-1-isopropyl-N-(4-
methy1-1,1-
dioxidotetrahydro-2H-thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
To a stirred solution of (R)-3-(2-(difluoromethoxy)-5-fluoropyridin-4-y1)-1-
isopropy1-4,5,6,7-
tetrahydro-1H-indazole-6-carboxylic acid (140 mg, 0.38 mmol) in DMF (3.8 mL)
was added
DIPEA (0.3 mL, 1.9 mmol), HATU (173 mg, 0.46 mmol), and 4-amino-4-
methyltetrahydro-2H-
thiopyran 1,1-dioxide hydrochloride (76 mg, 0.38 mmol). The reaction mixture
was stirred at rt
for 25 min. The reaction mixture was filtered and purified by mass triggered
reverse phase
HPLC (ACN/water with 0.1% FA modifier) to afford the title compound. LC/MS =
515 [M+1].
1H NMR (500 MHz, Chloroform-d) 6 8.04 (d, J = 1.6 Hz, 1H), 7.53 - 7.21 (t, J =
73.2 Hz, 1H),
7.22 (s, 1H), 5.36 (s, 1H), 4.41 (p, J = 6.6 Hz, 1H), 3.14- 3.04 (m, 2H), 3.03
-2.93 (m, 3H),
2.93 - 2.80 (m, 2H), 2.76 - 2.51 (m, 5H), 2.26 (t, J = 12.3 Hz, 2H), 2.07 (d,
J = 12.9 Hz, 1H),
1.83 (td, J = 11.6, 5.8 Hz, 1H), 1.54 - 1.50 (m, 6H), 1.50 (s, 3H). DGAT2 1050
(nM) = 43,8,
By using procedures similar to those described in Example 21 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
DGAT2
LCMS
Example Structure Name
IC50
[M+1]
(nM)
(R)-3-(2-ethoxy-5-fluoropyridin-4-
N
F \ y1)-1-isopropyl-N-(4-methyl-1,1-
22 H IµN dioxidotetrahydro-2H-thiopyran-4- 493
144.0
o y1)-4,5,6,7-tetrahydro-1H-indazole-
0
6-carboxamide
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(R)-3 -(3 -(difluoromethoxy)pheny1)-
=
orF
N-(3-methy1-1,1 -dioxidothietan-3-
23 j H µ,NI y1)-1-(tetrahydro-2H-pyran-4-y1)-
510 168.8
N
oP
4,5,6,7-tetrahy dro-1H-ind azol e-6-
0
carb oxami de
(R)-3 -(3 -(difluoromethoxy)pheny1)-
or 1-(1,1-di oxi dotetrahy dro-2H-
24 's,k1 thiopyran-4-y1)-N-(0-3-methy1-1,1-
572
144.5
0(g. 0 b di oxi dotetrahy drothi ophen-3-y1)-
4,5,6,7-tetrahy dro-1H-ind azol e-6-
0
carb oxami de
(R)-3 -(3 -(difluoromethoxy)pheny1)-
C))--F 1-isopropyl-N-((S)-3-methyl-1,1-
25 r id i N di oxi dotetrahy drothi ophen-3-y1)-
482 59.8
05C 1r 1)¨ 4,5,6,7-tetrahy dro-1H-ind azol e-6-
0'
carb oxami de
(R)-3 -(3 -(di fl uorometh oxy)ph eny1)-
* or
1 -isopropyl-N-(3-methy1-1,1-
26 j)idi oxi dothi etan-3-y1)-4,5,6,7- 468
318.9
oP Ite
tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(3 -(difluoromethoxy)pheny1)-
F F 1-(tetrahy dro-2H-pyran-4-y1)-N-(2-
27 F Ap, N=,N
(6-(trifluoromethyl)py ri din-3- 579
128.0
yl)propan-2-y1)-4,5,6,7-tetrahydro-
1H-indazole-6-carboxamide
(R)-3 -(difluoromethoxy)-2-
fluoropheny1)-1-is opropyl-N-((S)-3-
F 41#
methyl-1,1 -
28 H µ,N 500
30.1
crinr dioxidotetrahy drothiophen-3-y1)-
4,5,6,7-tetrahydro-1H-indazol e-6-
carboxamide
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(R)-3 -(difluoromethoxy)-2-
fl uoropheny1)-1-is opropyl-N-((R)-3-
F
methyl-1,1 -
29 .0 500
60.1
di oxi dotetrahy drothi ophen-3-y1)-
031= =

0 J N
).'"-
0' 4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami de
(R)-3 -(5 -(difluoromethoxy)-2-
F = C))---F fluoropheny1)-1-isopropyl-N-(4-
30 H %, methyl-1,1-dioxidotetrahydro-2H-
514 5.5
N
0e56 thiopyran-4-y1)-4,5,6,7-tetrahydro-
1H-indazole-6-carboxamide
(R)-3 -(3 -(difluoromethoxy)pheny1)-
OrF 1 ¨i opropyl-N-(4-methy1-1,1-
31 H 51`pi di oxi dotetrahy dro-2H-thi opy ran-4-
496 24.7
404 N
0 ,ek¨ y1)-4,5,6,7-tetrahy dro-1H-indazol e-
0
6- carb oxamide
(R)-3 -(3 -cy cl oprop oxyph eny1)-1-
= (")?, i s opropyl-N-(4-methy1-1,1 -

32 11 el 1 µ,N di oxi dotetrahy dro-2H-thi opy ran-4-
486 29.1
N
y1)-4,5,6,7-tetrahydro-1H-indazole-
e
6- carb oxamid e
(R)-3 -(3 -ethoxypheny1)-1-i s opropy 1-
N-(4-methy1-1,1 -di oxi d otetrahy dro-
33 5i %pi 2H-thiopyran-4-y1)-4,5,6,7- 474
3.3
00 r
tetrahy dro-1H-indaz ol e-6-
carb ox ami de
(R)-3 -(2-ethoxy-5-fluoropyri din-4-
F I y1)-1-isopropyl-N-(3-methy1-1,1-
34 I N di oxi dothi etan-3 465
117.3
N
01 tetrahy dro-1H-indazole-6-
carb ox ami de
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(R)-1-isopropyl-N-(0-3-methy1-
1,1-dioxidotetrahydrothiophen-3-
*
y1)-3-(3-(2,2,2-
35 H 1101 I ",1,4 514
35.2
trifluoroethoxy)pheny1)-4,5,6,7-
0(
tetrahydro-1H-indazole-6-
carboxamide
(R)-1-isopropyl-N-(4-methyl- 1,1-
14 0, dioxidotetrahydro-2H-thiopyran-4-
FinF

3 6 H 1101 546
353
N tetrafluoroethoxy)pheny1)-4,5,6,7-
0.sõ, g )--
c?
tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(2-cyclopropoxy-5-
N fluoropyridin-4-y1)-1-isopropyl-N-
/
F (4-methy1-1,1-dioxidotetrahydro-
37 H I 'µN 505
93.2
N 2H-thiopyran-4-y1)-4,5,6,7-
ow.õ... 0

o tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(5-fluoro-2-
:1 isopropoxypyridin-4-y1)-1 -
F /.µ
isopropyl-N-(4-methyl-1,1-
38 H I N 507
74.3
dioxidotetrahydro-2H-thiopyran-4-
ord-NT
v1)-4,5,6,7-tetrahydro-1H-indazole-
6-carboxamide
(R)-3-(5-chloro-2-ethoxypyridin-4-
= o ,, y1)-1-isopropyl-N-(4-methy1-
1,1-
39 H I =N dioxidotetrahydro-2H-thiopyran-4-
509 7.7
050-NT
y1)-4,5,6,7-tetrahydro-1H-indazole-
6-carboxamide
N F (R)-3-(2-(2,2-difluoroethoxy)-5-

fluoropyridin-4-y1)-1-isopropyl-N-
40 H I µ1,1 529
4.6
(4-methy1-1,1-dioxidotetrahydro-
OV.,.. 0
0 2H-thiopyran-4-v1)-4,5,6,7-
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tetrahy dro-1H-indaz ol e-6-
carb oxami de
(R)-3-(2-(difluoromethoxy)-5-
N fluoropyridin-4-y1)-1 -is opropy 1-N-
F I
((5)-3-methy 1- 1 ,1-
41 H I NN 501
138.6
l
di oxi dotetrahy drothi ophen-3-y1)-
oo t " ,
4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami de
(R)-3 -(5 -(difluoromethoxy)-2-
(difluoromethyppyri din-3-y1)-1 -
F Or
opropyl-N-(4-methy l-1,1 -
42 H µ,I4 547
296.2
(NyN di oxi d otetrahy dro-2H-thi opy ran-4-
0 y1)-4,5,6,7-tetrahy dro-1H-indazol e-
6- carb oxamide
(R)-3 -(5 -fl uoro-2-(2,2,2-
trifluoroethoxy)pyri din-4-y1)-1 -
F NI\ --CF,
isopropyl-N-(3-methyl-1 ,1 -
43 I Np 519
14.1
ri.Nstr N
di oxi dothi etan-3 -y1)-4,5,6,7-
o tetrahy dro-1H-indaz ol e-6-
carb oxami de
(R)-3 -(5 -fl uoro-2-(2,2,2-
trifluoroethoxy)pyri din-4-y1)-1
Nµ
44 H
isopropyl -N-45)-3 -methy 1-1,1 -
_ I N 533
5.3
di oxi dotetrahy drothi ophen-3-y1)-
0503 NT
o 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(5 -fluoro-2-(2,2,2-
trifluoroethoxy)pyri din-4-y1)-1
Nµ ¨cF,
is opropyl-N-(4-methy l-1,1 -
45 H I µ,NI 547
18.4
di oxi do te trahy dro-2H-thi opy ran-4-
ow,õ,,, 0
0 y1)-4,5,6,7-tetrahy dro-1H-indazol e-
6- carb oxamide
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(R)-3-(5-(difluoromethoxy)-2-
F rF fluoropheny1)-N-(4-methyl-1,1-
dioxidotetrahydro-2H-thiopyran-4-
46 521
37.9
(j DN D
y1)-1-(propan-2-yl-d7)-4,5,6,7-
DD DD
tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(2-ethoxy-5-fluoropyridin-4-
y1)-N-(4-methy1-1,1 -
dioxidotetrahydro-2H-thiopyran-4-
47 rJ<Ed.ir NN."
0 500
65.9
Dx\--(-DD y1)-1-(propan-2-yl-d7)-4,5,6,7-
01 D D D tetrahydro-1H-indazole-6-
carboxamide
(6R)-3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-(1,1-
F C)rF difluoropropan-2-y1)-N-(3-methyl-
48a HSi ,NN 1,1-dioxidothietan-3-y1)-4,5,6,7-
522 90.3
N 1-8 F
s /1---( tetrahydro-1H-indazole-6-
0
carboxamide (faster eluting with
OD-H column, 20% iPrOH/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-(1,1-
F ai Or difluoropropan-2-y1)-N-(3-methyl-
48b H 11011 1 N,N 1,1-dioxidothietan-3-y1)-4,5,6,7-
522 19.8
4N,õ. N
A )--(F tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
OD-H column, 20% iPrOH/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
fluorophenv1)-1-(1,1-
F C)F
..._
difluoropropan-2-y1)-N-(4-methyl-
49a III I N,NI 550
32.1
N F 1,1-dioxidotetrahydro-2H-thiopyran-
O3,e 0
0
F
4-y1)-4,5,6,7-tetrahydro-1H-
indazole-6-carboxamide (faster
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eluting with OD-H column, 20%
Et0H/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-(1,1-
difluoropropan-2-y1)-N-(4-methyl-
F = ?"--F
1, 1-dioxidotetrahy dro-2H-thiopyran-
49b H 0101 I µ, 550
0.6
N F
OV..õ.= 0 4-y1)-4,5,6,7-tetrahydro-1 H-
O F indazole-6-carboxamide (slower
eluting with OD-H column, 20%
Et0H/CO2)
(R)-3-(2-(ethoxy-d5)-5-
NI 0 D fluoropyridin-4-y1)-1-isopropyl-N-
F
(4-methy1-1,1-dioxidotetrahydro-
50 H I k N 498
51.0
2H-thiopyran-4-y1)-4,5,6,7-
0 }-
0
tetrahydro-1H-indazole-6-
carboxamide
(R)-N-(4-cyano-1,1-
di oxi d otetrahydro-2H-thi opy ran -4-
F
y1)-3-(5-(difluoromethoxy)-2-
51 D
532
4.3
D
D D fluoropheny1)-1-(propan-2-yl-d7)-
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)-N-(4-cyano-1,1 -
F 0)-.* F dioxidotetrahydro-2H-thiopyran-4-
y1)-3-(5-(difluoromethoxy)-2-
52 8,4
525
4.7
ki-ror
fluoropheny1)-1-isopropy1-4,5,6,7-
o
o tetrahydro-1H-indazole-6-
carboxamide
(6R)-3-(2-ethoxy-5-fluoropyridin-4-
y1)-N-(4-methyl-1,1-
53a H I k N 547
162.1
F
dioxidotetrahydro-2H-thiopyran-4-

y1)-1-(1,1,1-trifluoropropan-2-y1)-
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4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (faster eluting with:
OD-H column, 20% Me0H/CO2)
(6R)-3-(2-ethoxy-5-fluoropyridin-4-
y1)-N-(4-methy1-1,1 -
N
F 1L o dioxidotetrahydro-2H-thiopyran-4-
53b H N y1)-1-(1,1,1-trifluoropropan-2-y1)-
547 10_33
Ny 0 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
OD-H column, 20% Me0H/CO2)
(R)-3-(5-ethoxy-2-fluoropheny1)-1-
F *o isopropyl-N-(4-methy1-1,1-
54 H 1 µ,ry dioxidotetrahydro-2H-thiopyran-4-
492 1.8
N N
o9p,- o )--"" y1)-4,5,6,7-tetrahydro-1H-indazole-
0
6-carboxamide
(R) - 1 - isopropyl-N-(4-methy1-1,1-
= 0?c..:
dioxidotetrahydro-2H-thiopyran-4-
55 H5i N y1)-3-(3-(trifluoromethoxy)pheny1)-
514 86.6
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(5 -(difl uoromethoxy)py ridin-
.C))-"F 3-y1)-1-isopropyl-N-(4-methyl-1,1-
56 H I `N dioxidotetrahydro-2H-thiopyran-4-
497 414
N'
0 VO-4,5,6,7-tetrahydro-1H-indazole-
6-carboxamide
(R)-1-cyclobuty1-3-(5-
F =C)r (difluoromethoxy)-2-fluoropheny1)-
57 H 4 µN N-(3-methyl-1,1-dioxidothietan-3-
498 22.8 N N
,
I y1)-4,5,6,7-tetrahydro-1H-indazole-
6-carboxamide
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(6R)-1-(1-cyclopropylethyl)-3-(5-
(difluoromethoxy)-2-fluoropheny1)-
r *
N-(3-methy1-1,1-dioxidothietan-3-
58a H \ 512
23.4
N N

y1)-4,5,6,7-tetrahydro-1H-indazole-
0'8
6-carboxamide (faster eluting with
IC column, 35% Me0H/CO2)
(6R)-1-(1-cyclopropylethyl)-3-(5-
(difluoromethoxy)-2-fluoropheny1)-
F OrF
N-(3 -methyl-1,1-dioxi dothietan-3-
58b H 1110 I =,N 512
2.5
y1)-4,5,6,7-tetrahydro-1H-indazole-
01
6-carboxamide (slower eluting with
IC column, 35% Me0H/CO2)
ethyl 3-((R)-3-(5-(difluoromethoxy)-
2-fluoropheny1)-1-isopropy1-4,5,6,7-
F * C\--F
tetrahy dro-1H-indaz ole-6-
59 I-1 523
61.0
carboxamido)-3-methylpyrrolidine-
1-carboxylate (mixture of
diastereomers)
(6R)-3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-isopropyl-N-(1-
FOF (isopropylcarbamoy1)-3-
60 H 101 µ,N methylpyrrolidin-3-y1)-4,5,6,7-
536 29.2
)--N F- N ¨ tetrahydro-1H-indazole-6-
carboxamide (mixture of
diastereomers)
(6R)-N-(1-(cyclopropanecarbony1)-
3-methylpyrrolidin-3-y1)-3-(5-
F
F (difluoromethoxy)-2-fluoropheny1)-
61 H SiN 519 26.2
N
1-is opropy1-4,5,6,7-tetrahy dro-1H-
indazole-6-carboxamide (mixture of
diastereomers)
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(R)-3 -(3 -(difluoromethoxy)pheny1)-
4itO
= 1 " F1 1 -isopropyl-N-(pyridin-3-
ylmethy 1)-
62 441
8188
4,5,6,7-tetrahy dro-1H-ind azol e-6-
r
) ,1
carb oxami de
(R)-3-(3-(difluoromethoxy)pheny1)-
F 1-isopropyl-N-(isoxazol-4-
63
)....,H µ,N 431
4561
Nr N ylmethyl)-4,5,6,7-tetrahydro-1H-
indazole-6-carboxamide
(6R)-3-(5-(difluoromethoxy)-2-
----
F C)t-F fluoropheny1)-1-is opropyl-N-(1 -
64 c)..Nr 01 `,N
isopropyl-2-oxopyrrolidin-3-y1)- 493 622
HN,Tro N
0 4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami de
(R)-3 -(3 -(difluoromethoxy)pheny1)-
N-((S)-1-hy droxy propan-2-y1)-1-
65 H 1110 I N 408
7263
Fin-Mor i s opropy1-4,5,6,7-tetrahy dro-1H-
indazol e-6-carbox ami de
(R)-3 -(3 -(difluoromethoxy)pheny1)-
* )--F 1-i s opropyl-N-(1-methoxy -2-
66 ,N
11110 methylpropan-2-y1)-4,5,6,7- 436 1329
.. I µ
tetrahy dro-1H-indazole-6-
carb oxami de
(R)-3 -(3 -(difluoromethoxy)pheny1)-
= (>--F N-(5 -methyl-1,3,4-thi adi
azol-2-y1)-
67 N H rsjµ 1-(tetrahydro-2H-pyran-4-y1)- 490
>10000
N7_,y N ir
\---6)
4,5,6,7-tetrahydro-1H-indazole-6-
carb oxami de
(R)-3 -(5 -(di fl uorom eth oxy)py ri din-
N
C)--F 3-y1)-1-is opropyl-N-(0-1 -((R)-2-
68 H I N methylmorpholino)propan-2-y1)-
492 >10000
91-Y11. 4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami de
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= 0 F
).... (R)-3-(3-(difluoromethoxy)pheny1)-
N-(3-ethy1-1,1-dioxidothietan-3-y1)-
69 2 en `,N 482
90
o 1 -isopropy1-4,5,6,7-tetrahydro-1H-
o
II
0 indazole-6-carboxamide
(R)-3-(3-(difluoromethoxy)pheny1)-
fik N-(2-(1,1-
70 11 = \ N dioxidothiomorpholino)ethyl)-1-
511 18010
0 isopropy1-4,5,6,7-tetrahydro-1H-
o= '
indazole-6-carboxamide
(R)-3-(3-(difluoromethoxy)pheny1)-
!It OF 1-isopropyl-N-(2-(N-
71 H methylsulfamoyDethyl)-4,5,6,7-
471 >10000
N
^ 0 ND 0 tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(3-(difluoromethoxy)pheny1)-
* N-((R)-3-methy1-1,1-
537
72 " µ," dioxidotetrahydrothiophen-3-y1)-1-
N
>10000
(1-methylpiperidin-4-y1)-4,5,6,7-
N
tetrahydro-1H-indazole-6-
carboxamide
(R)-1-acety1-3-(3-
(difluoromethoxy)pheny1)-N-(0-3-
= (3)¨F
methyl-1,1- 482
>10000
dioxidotetrahydrothiophen-3-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R) -1-(cyclopropanecarbony1)-3-(3-
44, (difluoromethoxy)pheny1)-N-((S)-3-
508
methyl-1,1-
"
74 o .01µ,
2914
0 dioxidotetrahydrothiophen-3-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
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(R)-3 -(3 -(difluoromethoxy)pheny1)-
N-((5)-3-methy1-1,1-
di oxi dotetrahy drothi ophen-3 -y1)-1- 552
75 SI
>10000
(tetrahy dro-2H-pyran-4-carbony1)-
4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami de
(R) -1-benzoy1-3-(3-
(difluoromethoxy)pheny1)-N-(($)-3-
*O
methyl-1,1-
76 'N 544
2739
0 010 I
* di oxi dotetrahy drothi ophen-3-y1)-
0
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R) -1-benzy1-3-(3-
(difluoromethoxy)pheny1)-N-(0-3-
= or
methyl-1,1- 530
3 H µ
r__:r.N I JV 577
N
di oxi dotetrahy drothi ophen-3-y1)-
77
d'4')
4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami de
(R)-3 -(3 -(difluoromethoxy)pheny1)-
N-((5)-3-methyl-1,1-
= or
di oxi d otetrahy drothi ophen-3 -y1)-1-
78 HSI \,N 538
>10000
N ((tetrahy dro-2H-py ran-4-yl)methyl )-

-5
\--Co
4,5,6,7-tetrahy dro-1H-ind azol e-6-
carb oxami de
(6R)-1-(1 -cyanoethyl)-3-(5-
(difl uoromethoxy)-2-fluoropheny1)-
F * \Fr F
N-(3 -methyl-1,1 -di oxi dothi etan-3-
79 czõ H op, 497 591
0=Vc,N,r. N y1)-4,5,6,7-tetrahy dro-1H-indazol e-
0
6- carboxamide (mixture of
di astereomers)
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(6R)-3-(5-(difluoromethoxy)-2-
fluoropheny1)-N-(3-methy1-1,1-
F *
dioxidothietan-3-y1)-1-(1-(thiazol-2-
80 _1-11 -0' ,='" 555
174
ypethyl)-4,5,6,7-tetrahydro-1H-
oq-ll
0 indazole-6-carboxamide (mixture of
diastereomers)
EXAMPLE 81
(R)-3-(2-fluoro-5-isopropoxypheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-
3-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxamide
SPA STEP B
ark 0 N
,0.1cr Fl"
C'Y
STEP C H CON STEP D
-Jo- I...Ls.. Si ,N
N'µ
s 8 Tor
01-8 e=-m
- Ex-81
STEP A: Methyl (R)-3-iodo-l-isopropy1-4,5,6,7-tetrahydro-1H-indazole-6-
carboxylate
To a mixture of methyl (R)-3-iodo-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate
(3.0 g, 9.8
mmol), 2-iodopropane (3.3 g, 6.5 mmol), Cs2CO3 (12.8 g, 39.2 mmol) was added
DMF (20 m1).
The mixture was stirred at 100 C, for 30 minutes. The reaction mixture was
cooled to rt and
water was added. The aqueous layer was extracted three times with Et0Ac. The
combined
organic layers were washed with water and brine. The organic layer was then
dried over MgSO4
(s), filtered, and concentrated in vacuo. The crude product was purified by
flash silica gel
column chromatography (20% Et0Ac in hexanes) to afford the title compound.
LC/MS = 349
[M+1].
STEP B: (R)-3-iodo-1-isopropy1-4,5,6,7-tetrahydro-1H-indazole-6-carboxylic
acid
To a mixture of methyl (R)-3-iodo-1-isopropy1-4,5,6,7-tetrahydro-1H-indazole-6-
carboxylate
(3.4 g, 9.8 mmol), LiOH (0.94 g, 39.3 mmol), THF (10.5 mL), Me0H (10.5 mL),
and water
(10.5 mL) were added. The mixture was stirred at rt for 25 minutes, then
acidified with 1N HC1
(aq.) to pH 1. The mixture was then extracted with Et0Ac, washed with water
and brine, dried
over MgSO4(s), filtered, and the volatiles evaporated to afford the title
compound. The crude
product was used without purification. LC/MS = 335 [M+11.
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STEP C: (R)-3-iodo-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-3-y1)-4,5,6,7-
tetrahydro-1H-
indazole-6-carboxamide
To a mixture of (R)-3-iodo-1-isopropy1-4,5,6,7-tetrahydro-1H-indazole-6-
carboxylic acid (3.1 g,
9.3 mmol) in DMF (13 mL) was added HATU (4.2 g, 11.2 mmol), DIPEA (6.5 mL,
37.2 mmol),
and then 3-amino-3-methylthietane 1,1-dioxide hydrochloride (1.76 g, 10.2
mmol). The mixture
was stirred at rt for 15 minutes. Then, water was added and the aqueous layer
was extracted three
times with Et0Ac. The combined organic layers were washed with water and
brine. The organic
layer was then dried over MgSO4(s), filtered, and concentrated in vacuo. The
crude product was
purified by flash silica gel column chromatography (70% Et0Ac in hexanes) to
afford the title
compound. LC/MS = 452 [M+1].
STEP D: (R)-3-(2-fluoro-5-isopropoxypheny1)-1-isopropyl-N-(3-methy1-1,1-
dioxidothietan-3-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
To a stirred solution of (R)-3-iodo-l-isopropyl-N-(3-methy1-1,1-dioxidothietan-
3-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxamide (100 mg, 0.22 mmol), (5-ethoxy-2-
fluorophenyl)boronic
acid (61 mg, 0.33 mmol), Pd(dpp0C12 (36 mg, 0.04 mmol), Na2CO3 (70.5 mg, 0.67
mmol), and
dioxane (1.1 mL) was added water (1.1 mL). The reaction mixture was sparged
with N2 for 5
min at rt then heated to 100 C for 15 min. After cooling to rt, the mixture
was filtered and
purified by mass triggered reverse phase HPLC (ACN/water with 0.1% FA
modifier) to afford
the title compound (Ex-81). LC/MS = 478 [M+11. 1H NMR (500 MHz, Chloroform-d)
6 7,09
(dd, J= 5.9, 3.1 Hz, 1H), 7.03- 6.98(m, 1H), 6.82 (dt, J= 8.9, 3.6 Hz, 1H),
6.49(s, 1H), 4.54 -
4.48 (m, 1H), 4.48 -4.42 (m, 1H), 4.37 (td, J= 12.8, 12.3, 6.1 Hz, 2H), 3.97
(ddd, J= 26.4,
13.9, 2.4 Hz, 2H), 2.82 - 2.60 (m, 2H), 2.57 (d, J = 5.7 Hz, 2H), 1.98 (q, J =
13.1, 9.9 Hz, 2H),
1.57 (s, 2H), 1.51 (dd, J= 33.0, 6.6 Hz, 6H), 1.35 - 1.29 (m, 6H). DGAT2 ICso
(nM) = 24.5.
By using procedures similar to those described in Example 81with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
DGAT2
LCMS
Example Structure Name
IC5o
[M+11
(nM)
F * Or (R)-3-(5-(difluoromethoxy)-2-
82 do Si N,N1
N
s 8 )--- fluoropheny1)-1-isopropyl-N-(3- 486
30.8
et
methy1-1,1-dioxidothietan-3-y1)-
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4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(5-cyclopropy1-2-
F * 4 fluoropheny1)-1-isopropyl-N-(3-
83 H 111011 µ,N methyl-
1,1-dioxidothietan-3-y1)- 460 46.0
N
8
0-8 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(2-chloro-5-
(difluoromethoxy)pheny1)-1-
c, s$,
isopropyl-N-(3-methy1-1,1-
84 dyll, AN N 502
7.92
dioxidothietan-3-y1)-4,5,6,7-00
tetrahydro-1H-indazole-6-
carboxamide
(R) - 3 -(5-cyclopropoxy-2-
F * (\c?, fluoropheny1)-1-isopropyl-N-(3-
85 methyl-1,1-dioxidothietan-3-y1)-
476 15.6
s 0 4,5,6,7-tetrahydro-1H-indazole-6-
oc-8
carboxamide
(R)-3-(5-(difluoromethoxy)-2-
7_= () methylpyridin-3-y1)-1-isopropyl-N-
86 cyr I r)_\ (3-methyl-1,1-dioxidothietan-3-y1)-
483 169.9
01-8 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(5-ethoxy-2,3-
F
F difluoropheny1)-1-isopropyl-N-(3-
87 , H SiN methyl-1,1-dioxidothietan-3-y1)-
482 3.6
TcSN ss. 4,5,6,7-tetrahydro-1H-indazole-6-
0-8
carboxamide
(R)-3-(2-chloro-5-
,, 7_\ )c-F
F F (trifluoromethoxy)pyridin-3-y1)-1-
88 NN 521
274.7
I
0<ly isopropyl-N-(3-methy1-1,1-
0
dioxidothietan-3-y1)-4,5,6,7-
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tetrahydro-1H-indazole-6-
carboxamide
(R)-N-(3,3-difluoro-1 -
me thylcy cl ob uty1)-3 -(5 -
; = 0,_
r F .. (difluoromethoxy)-2-
89 H I \ N 469
318.0
methy 1py ri din-3-y1)-1-is opropyl-
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)- 1 s opr opy 1- N - (3 -methyl-1,1-
,P
F3C
dioxidothietan-3-y1)-3-(3-(1 -
90 (trifluoromethyl)cyclopropyl)pheny 510
>10000
el I µ.14
1)-4,5 ,6,7-tetrahydro-1H-indazole-
=s N H
0 q.
6-carb oxami de
(R)-3-(3-(1 -
C N cy anocyclopropyl)pheny1)-1
s opropyl-N-(3-methy1-1,1 -
91 le N 467
>10000
0 Qr. N. di oxi dothi etan-3-y1)-4,5,6,7-
dsq. N H
tetrahydro-1H-indazole-6-
carboxamide
(R)-3-(2-(1,1-difluoroethyl)-5
N F F fluoropyridin-4-y1)-1-isopropyl-N-
F
(4-methyl-1,1-di oxi dotetrahy dro-
92 H I \ N 513
1214
N 2H-thi opyran -4-y1)-4,5 ,6,7-
0
)---
e tetrahydro-1H-indazole-6-
carboxamide
(R)- 1 -i sopropyl-N-(3-methy1-1,1-
* di oxi dothi etan-3-y1)-3 -(2-
93 I .1 1 Si µ,N methylbenzo [al oxazol-4-y1)-
457 >10000
s---1-1r
s o- 4,5,6,7-tetrahydro-1H-indazole-6-
01-..
0
carboxamide
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(R)-3 -(3 -(cy anomethyl)pheny1)-1 -
C N
opropyl-N-(3-methy 1-1,1 -
94 0111 I S.N dioxidothietan-3-y1)-4,5,6,7-
441 >10000
ot=
tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(tert-
butylcarbamoyppyridin-3-y1)-1 -
N
s opropyl-N-(3-methy1-1,1 -
95 502
>10000
o N,N1 dioxidothietan-3-y1)-4,5,6,7-
Okcci: tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(3 -(cy anomethoxy)pheny1)-1-
vr_ is opropyl-N-(3-methy1-1,1 -
96
N'N dioxidothietan-3-y1)-4,5,6,7- 457
>10000
OV NH 3- tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(3 -(1H-pyrazol -1-yl)pheny1)-
d7r),
1-i s opropyl -N-(3-methy1-1 ,1 -
97 =\' dioxidothietan-3-y1)-4,5,6,7- 468
>10000
0 N
tetrahydro-1H-indazole-6-
carboxamide
(R)-1-isopropyl-N-(3-methyl- 1,1 -
,I1L
dioxidothietan-3-y1)-3-(3-
98
0 I (methylsulfonyl)pheny1)-4,5,6,7-
480 >10000
N
0=I3,NH )-- tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(3 -(N-
(40 ethyl s ulfamoyl)pheny1)-1-
*
s opropyl-N-(3-methy1-1,1 -
99 0,
dioxidothietan-3-y1)-4,5,6,7- 509
>10000
9, OyP N
0%54, NH
tetrahydro-11-1-indazol e-6-
carboxamide
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(R)-3 -(5 -ethy1-2-fluoropheny1)-1-
F is opropyl-N-(3-methy 1-1,1 -
100 le I dioxidothietan-3-y1)-4,5,6,7- 448
158
0.
y
0 tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(5 -cy ano-2-fluoropheny1)-1-
NC *
is opropyl-N-(3-methy1-1,1 -
101 I \' dioxidothietan-3-y1)-4,5,6,7- 445
>10000
0-2s3, r!i H tetrahydro-1H-indazole-6-
carboxamide
(R)-3 -(3 -(1,1-difluoroethyl)pheny1)-
* F 1 -is opropyl-N-(3-methy1-1 ,1 -
102 I-1 el s',N dioxidothietan-3-y1)-4,5,6,7- 466
8840
tetrahydro-1H-indazole-6-
.5
0
carboxamide
(R)-N-(3,3-difluoro-1-
HO
* = methyl cycl obuty1)-3-(3-(1-
103 H µ,N hydroxycyclobutyl)pheny1)-1- 458
>10000
N
is opropy1-4,5,6,7-tetrahy dro-1
indazole-6-carboxarnide
Example 104
(R)-1 s opropyl-N-(3 -m ethy1-1,1 -di oxi doth etan-3-y1)-3 -(5-(1 ,1,2,2-
tetrafl uoro eth oxy)pyri
y1)-4,5,6,7 -tetrahy dro-1H-indazol e-6-carb oxami de
STEP A STEP B
F>CFFBr
STEP C
I N I NN I NN
./CLir
0 ,0y=
0 I
0 )S-
1)1 (F) F FF STEP E F F FF STEP F
STEP D
IN
,
µ.1q H ,N
(7).1t0 N
0 Hoy N
0

EX-104
STEP A: methyl (R)-3 -(5 -(b enzyl oxy)py ri din-3 -y1)-1 s opropy1-4,5,6,7-
tetrahy dro-1H-indazole-
6-carb oxylate
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To a solution of (R)-methyl 3-(5-(benzyloxy)pyridin-3-y1)-4,5,6,7- tetrahydro-
1H-indazole-6-
carboxylate (200 mg, 0.550 mmol) in DMF (5 mL) was added 2-iodopropane (187
mg, 1.1
mmol) and Cs2CO3 (538 mg, 1.651 mmol). The mixture was stirred at 50 C for 16
hrs. LCMS
showed that desired product was formed. The mixture was poured into H20, and
then the
mixture was extracted with Et0Ac (x 3). The combined organic layers were
washed with brine,
dried over Na2SO4, and then filtered and concentrated under reduced pressure.
The residue was
purified by column chromatography on silica (0-100% Et0Ac/hexanes) to afford
the title
compound. LC/MS = 406 [M+11.
STEP B: methyl (R)-3-(5-hydroxypyridin-3-y1)-1-isopropy1-4,5,6,7-tetrahydro-1H-
indazole-6-
carboxylate
A mixture of (R)-methyl 3-(5-(benzyloxy)pyridin-3-y1)-1-isopropyl- 4,5,6,7-
tetrahydro-1H-
indazole-6-carboxylate (170 mg, 0.419 mmol) and Pd/C (44.6 mg, 0.042 mmol) in
Me0H (10
mL) was stirred at 20 C for 30 mins. LCMS showed that desired compound was
formed. The
mixture was poured into ethyl acetate, through filter, then the filter cake
was dissolved in ethyl
acetate, dried over Na2SO4, and then filtered and concentrated under reduced
pressure to afford
the title compound. LC/MS = 316 [M+1].
STEP C: methyl (R)-3-(5-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridin-3-y1)-1-
isopropyl-4,5,6,7-
tetrahydro-1H-indazole-6-carboxylate
A 10 mL tube was charged with Cs2CO3 (62 mg, 0.19 mmol), (R)-methyl 3-(5-
hydroxypyridin-
3-y1)-1-isopropyl-4,5,6,7-tetrahydro-1H-indazole- 6-carboxylate (40 mg, 0.127
mmol) and 1,2-
dibromo-1,1,2,2-tetrafluoroethane (0.033 mL, 0.254 mmol) in DMSO (2 mL). Then
the mixture
was stirred at 50 'V for 2 hrs. LCMS showed that desired product was formed.
The mixture was
poured into H20, and the mixture was extracted with ethyl acetate (x 3). The
combined organic
layers were washed with brine, dried over Na2SO4, and then filtered and
concentrated under
reduced pressure to afford the title compound. LC/MS = 494/496 [114+11.
STEP D: methyl (R)-1-isopropy1-3-(5-(1,1,2,2-tetrafluoroethoxy)pyridin-3-y1)-
4,5,6,7-
tetrahydro-1H-indazole-6-carboxylate
A mixture of (R)-methyl 3-(5-(2-bromo-1,1,2,2- tetrafluoroethoxy)pyridin-3-y1)-
1-isopropy1-
4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (60 mg, 0.121 mmol) and zinc (24
mg, 0.364
mmol) in HOAc (5 mL) was stirred at 60 C for 3 hrs. LCMS showed that desired
compound
was formed. The mixture was dissolved in H20. Na1-ICO3 was added to the
mixture until pH = 7.
Then the mixture was extracted with ethyl acetate (x 3). The combined organic
layers were
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washed with brine, dried over Na2SO4, and then filtered and concentrated under
reduced pressure
to afford the title compound. LC/MS = 416 [M+1].
STEP E: (R)-1-isopropy1-3-(5-(1,1,2,2-tetrafluoroethoxy)pyridin-3-y1)-4,5,6,7-
tetrahydro-1H-
indazole-6-carboxylic acid
A mixture of LiOH=H20 (15 mg, 0.36 mmol) and (R)-methyl 1-isopropy1-3-(5-
(1,1,2,2-
tetrafluoroethoxy)pyridin-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate
(50 mg, 0.12
mmol) in Me0H (1 mL)/Water (1 mL)/THF (1 mL) was stirred at 40 C for 1 hr.
LCMS showed
that desired target was formed. The mixture was concentrated under reduced
pressure and was
dissolved in H20. HCl (1N in water) was added to the mixture until pH = 5.
Then the mixture
was extracted with ethyl acetate (x 3). The combined organic layers were
washed with brine,
dried over Na2SO4, and then filtered and concentrated under reduced pressure
to afford the title
compound. LC/MS = 402 [M+11
STEP F: (R)-1-isopropyl-N-(3-methy1-1,1-di oxidothi etan-3-y1)-3-(5-(1,1,2,2-
tetrafluoroethoxy)pyridin-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
A mixture of 2-(3H41,2,31triazo1o[4,5-blpyridin-3-y1)-1,1,3,3-
tetramethylisouronium
hexafluorophosphate(V) (91 mg, 0.239 mmol), N-ethyl-N -isopropylpropan-2-amine
(0.1 mL,
0.598 mmol), 3-amino-3-methylthietane 1,1-dioxide (24.25 mg, 0.179 mmol) and
(R)-1-
isopropy1-3-(5-(1,1,2,2- tetrafluoroethoxy)pyridin-3-y1)-4,5,6,7-tetrahydro-1H-
indazole-6-
carboxylic acid (48 mg, 0,120 mmol) in DMF (1 mL) was stirred at 25 C for 30
mins. LCMS
showed that desired product was formed. The residue was purified by mass
triggered reverse
phase HPLC (ACN/vvater with 0.1% TFA modifier) to afford EX-61. LC/MS = 519
[M+1]. 1H
NMR (400 MHz, METHANOL-d4) .5 8.70-8.89 (m, 2H), 8.45 (br s, 1H), 8.05 (s,
1H), 6.41-6.57
(m, 1H), 4.48-4.55 (m, 1H), 4.38-4.47 (m, 2H), 4.11-4.18 (m, 2H), 2.76-2.94
(m, 4H), 2.67-2.74
(m, 1H), 2.10-2.18 (m, 1H), 1.77-1.87 (m, 1H), 1.73 (s, 3H), 1.48 (d, J=6.60
Hz, 6H). Human
DGAT2 IC50 = 1000 nM
By using procedures similar to those described in Example 104 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
LCMS DGAT2
Example Structure Name
[M+ll ICso (nM)
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(R)- 1 -i sopropyl-N-((S)-3-methyl-
, 1,1-dioxidotetrahydrothiophen-3-
1 F5rF.--1`F y1)-3-(5-(1,1,2,2-
105 H N
533 117.8
I
tetrafluoroethoxy)pyridin-3-y1)-
05,3 8
4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide
(R)- 1 -isopr opyl- N - (4 - methy 1- 1,1¨
F dioxidotetrahydro-2H-thiopyran-4-
7 F5F(F y1)-3-(5-(1,1,2,2-
106 H N 547
203.7
lot=1õ..1 N tetrafluoroethoxy)pyridin-3-y1)-
4,5,6,7-letrahydro-1H-indazole-6-
carboxamide
EXAMPLE 107
(6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-y1)-1-(3-hydroxy-3-
methylbutan-2-y1)-N-(4-
methy1-1,1-dioxidotetrahydro-2H-thiopyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-
6-
carboxamide
F F C)\--CF, F Niµ
\ N STEP A \ N STEP B \ N STEP C
Me0 Me0 so N' HO
H
D
I µN STEP 111 I µ,N
HOT N==
Ofj )1
OH
0 OH
EX-107
STEP A: Methyl (6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-y1)-1-(3-
oxobutan-2-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-carboxylate
To a stirred solution of methyl (R)-3-(5-fluoro-2-(2,2,2-
trifluoroethoxy)pyridin-4-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxylate (360 mg, 0.96 mmol), 3-bromobutan-2-one
(218 mg, 1.45
mmol), and DMF (2.8 mL) was added Cs2CO3 (0.94 g, 2.89 mmol). The mixture was
stirred at
80 C for 30 minutes. The reaction mixture was cooled to rt and water was
added. The aqueous
layer was extracted three times with Et0Ac. The combined organic layers were
washed with
water and brine. The organic layer was then dried over MgSO4(s), filtered, and
concentrated in
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vacuo. The crude product was purified by flash silica gel column
chromatography (0-70%
Et0Ac in hexanes) to afford the title compound. LC/MS = 444 [M+1].
STEP B: (6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-y1)-1-(3-oxobutan-
2-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxylic acid
To a mixture of methyl (6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-y1)-
1-(3-oxobutan-2-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (329 mg, 0.74 mmol),and LiOH
(71 mg, 2.97
mmol), was added THF (1.6 mL), Me0H (0.5 mL), and water (1.6 mL). The mixture
was stirred
at rt for 10 minutes, then acidified with concentrated HC1 to pH 1. The
mixture was extracted
with Et0Ac. The combined organic layers were washed with water and brine,
dried over MgSO4
(s), filtered, and the volatiles were evaporated to afford the title compound.
The crude product
was used without purification. LC/MS = 430 [M+11.
STEP C: (6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-y1)-1-(3-hydroxy-3-
methylbutan-2-
y1)-4,5,6,7-tetrahydro-1H-inda7ole-6-carboxylic acid
At 0 C, to a mixture of (6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-
y1)-1-(3-oxobutan-2-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid (319 mg, 0.74 mmol) and
THF (4.9 mL)
was added methylmagnesium bromide (1.5 mL, 4.5 mmol, 3.0 M in Et20). The
mixture was
stirred at 0 C for 10 minutes. Water was added, and the mixture was acidified
with concentrated
HC1 to pH 1. The aqueous layer was extracted three times with Et0Ac. The
combined organic
layers were washed with water and brine. The organic layer was then dried over
MgSO4(s),
filtered, and concentrated in vacuo. The crude product was used without
purification. LC/MS =
446 IM-F11.
STEP D: (6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-y1)-1-(3-hydroxy-3-
methylbutan-
2-y1)-N-(4-methy1-1,1-dioxidotetrahydro-2H-thiopyran-4-y1)-4,5,6,7-tetrahydro-
1H-indazole-6-
carboxamide
To a mixture of (6R)-3-(5-fluoro-2-(2,2,2-trifluoroethoxy)pyridin-4-y1)-1-(3-
hydroxy-3-
methylbutan-2-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid (100 mg,
0.23 mmol) in
DCM (0.6 mL) was added HATU (102 mg, 0.27 mmol), DIPEA (137 uL, 0.79 mmol),
and then
(4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (54 mg,
0.27 mmol). The
mixture was stirred at rt for 1 h. The mixture was purified by flash silica
gel column
chromatography (0-80% Et0Ac in hexanes) to afford the title compound. LC/MS =
591 IM+11.
The mixture of two stereoisomers was purified by chiral preparative SFC (OD-H
column, 25%
Et0H/CO2) to afford Ex-107a (faster eluting) and Ex-107b (slower eluting). Ex-
107a (faster
eluting): 1-1-1NMR (500 MHz, Methanol-d4) 6 8.09 (d, J= 2.0 Hz, 1H), 7.07 (d,
J= 4.9 Hz, 1H),
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4.85 (q, 2H), 4.25 (q, J= 6.9 Hz, 1H), 3.24¨ 3.12 (m, 2H), 3.03 ¨2.94 (m, 3H),
2.88 ¨2.62 (m,
6H), 2.17 ¨ 2.03 (m, 3H), 1.84¨ 1.74 (m, 1H), 1.53 (d, J= 6.9 Hz, 3H), 1.44
(s, 3H), 1.24 (s,
3H), 1.14 (s, 3H).
By using procedures similar to those described in Example 107 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
DGAT2
LCMS
Example Structure Name
ICso
[M+1]
(nM)
(6R)-3-(5-fluoro-2-(2,2,2-
trifluoroethoxy)pyridin-4-y1)-1-
(3-hydroxy-3-methylbutan-2-y1)-
F -'4"FF N-(4-methy1-1,1-
107a di I \ dioxidotetrahydro-2H-thiopyran- 591
3.9
Nlor ), 4_
4-y1)-4,5,6,7-tetrahydro-1
0 H
mdazole-6-carboxamide (faster
eluting with OD-H column, 25%
Et0H/CO2)
(6R)-3-(5-fluoro-2-(2,2,2-
trifluoroethoxy)pyridin-4-y1)-1-
(3-hydroxy-3-methylbutan-2-y1)-
F /-1:1µ N-(4-methy1-1,1-
107b di I µ,NI dioxidotetrahydro-2H-thiopyran- 591
5.4
NIcr N
4-y1)-4,5,6,7-tetrahy dro- 1H-
OH
0
indazole-6-carboxamide (slower
eluting with OD-H column, 25%
Et0H/CO2)
(6R)-3-(2-ethoxy -5 uoropy ri din-
F o\--" 4-y1)-1-(3-hydroxy-3-
108a = H I N methylbutan-2-y1)-N-((5)-3- 523
44.1
1)14" methyl-1,1 -
OH
dioxidotetrahydrothiophen-3-y1)-
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4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (faster eluting with
OD-H column, 15% Me0H/CO2)
(6R)-3-(2-ethoxy -5 -fl uoropy ridin-
4-y1)-1-(3 droxy
methylbutan-2-y1)-N-(0-3-
F
methyl-1,1-
108b H I 'µ,N 523
172.5
dioxidotetrahydrothiophen-3-y1)-
ICN0
O OH 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
OD-H column, 15% Me0H/CO2)
(6R)-3-(2-ethoxy-5-fluoropyridin-
4-y1)-1-(3 droxy
methylbutan-2-y1)-N-(4-methyl-
F
1,1-dioxidotetrahydro-2H-
109a H I N 537
49.5
thiopyran-4-y1)-4,5,6,7-
0
O OH tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
OJ-H column, 10% Me0H/CO2)
(6R)-3-(2-ethoxy-5-fluoropyridin-
4-y1)-1-(3-hydroxy -3-
methylbutan-2-y1)-N-(4-methyl-
/
1,1-dioxidotetrahydro-2H-
109b H I µN 537
30.7
thiopyran-4-y1)-4,5,6,7-
0=s -
O OH tetrahydro-1H-indazole-6-
carboxamide (faster eluting with
OJ-H column, 10% Me0H/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
F O.F fluoropheny1)-1-(3-hydroxy-3-
110a rydlor Si methylbutan-2-y1)-N-(3-methyl-
530 30.8
OH 1,1-dioxidothietan-3-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-
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carboxamide (faster eluting with
OD-H column, 15% Me0H/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
uoropheny1)-1-(3-hy droxy -3 -
F * Or methylbutan-2-y1)-N-(3-methyl-
110b S 1,1-dioxidothietan-3-y1)-4,5,6,7-
530 243.4
) tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
OD-H column, 15% Me0H/CO2)
(6R)-3-(3-
(difluoromethoxy)pheny1)-1-(3-
. hydroxy-3-methylbutan-2-y1)-N-
(4-methyl- ,1-di oxi dotetrahy dro-
111a (Sir 51 "
2H-thiopyran-4-y1)-4,5,6,7- 540
2066
OH
tetrahydro-1H-indazole-6-
carboxamide (faster eluting with
IC column, 30% iPrOH/CO2)
(6R)-3-(3-
(difluoromethoxy)pheny1)-1-(3 -
jo or hydroxy-3-methylbutan-2-y1)-N-
(4-methy1-1,1-dioxidotetrahydro-
111b 540
229.6
g )4- 2H-thiopyran-4-y1)-4,5,6,7-
OH
tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
IC column, 30% iPrOH/CO2)
(6R)-3-(5-fluoro-2-(2,2,2-
trifluoroethoxy)pyridin-4-y1)-1 -
(3-hydroxy-3-methylbutan-2-y1)-
N F F
N-((S)-3-methy1-1,1 -
112a H I NN 577
11.3
dioxidotetrahydrothiophen-3-y1)-
O 'orrs
OH 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (faster eluting with
OD-H column, 15% Et0H/CO2)
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(6R)-3-(5-fluoro-2-(2,2,2-
trifluoroethoxy)pyridin-4-y1)-1-
H %NiN F (3-hydroxy-3-methylbutan-2-y1)-
F
OF
N-((5)-3-methyl-1,1-
112b 577
31.6
N CC9- dioxidotetrahydrothiophen-3-y1)-
0.0 TO i)t+
OH 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
OD-H column, 15% Et0H/CO2)
(6R)-N-(4-cyano-1,1-
dioxidotetrahydro-2H-thiopyran-
4-y1)-3-(5-fluoro-2-(2,2,2-
F
N trifluoroethoxy)pyridin-4-y1)-1-
113 a `,N 602
27.8
(3-hydroxy-3-methylbutan-2-y1)-
0 OH
0 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (faster eluting with
OD-H column, 12% Et0H/CO2)
(6R)-N-(4-cyano-1,1-
dioxidotetrahydro-211-thiopyran-
, 4-y1)-3-(5-fluoro-2-(2,2,2-
trifluoroethoxy)pyridin-4-y1)-1-
113b IIIi `,N 602
70.3
N
g (3-hydroxy-3-methylbutan-2-y1)-
eS OH
Oni
0 4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (slower eluting with
OD-H column, 12% Et0H/CO2)
EXAMPLE 114
(6R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-1-(2-hydroxycyclopenty1)-N-(3-
methyl-1,1-
dioxidothietan-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
F Or F OFF
STEP B
dah .0,
tro ,d,
0-g OH
0*-8
EX-114
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STEP A: (6R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-N-(3-methy1-1,1-
dioxidothietan-3-y1)-1-
(2-oxocyclopenty1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
To a stirred solution of (R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-N-(3-
methy1-1,1-
dioxidothietan-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide (110 mg,
0.25 mmol), 2-
bromocyclopentan-1-one (81 mg, 0.50 mmol), and DMF (0.7 mL) was added K2CO3
(103 mg,
0.74 mmol). The mixture was stirred at 60 C. for 24 hours. The reaction
mixture was cooled to rt
and directly purified by flash silica gel column chromatography (0-70%
Et0Ac/hexanes) to
afford the title compound. LC/MS = 526 [M+11.
STEP B: (6R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-1-(2-hydroxycyclopenty1)-N-
(3-methyl-
1,1-dioxidothietan-3-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
At 0 C, to a mixture of (6R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-N-(3-
methy1-1,1-
dioxidothietan-3-y1)-142-oxocyclopentv1)-4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (66
mg, 0.13 mmol) in Me0H (1.2 mL) was added sodium borohydride (14 mg, 0.38
mmol). The
mixture was stirred at 0 C for 1.5 hours. Sat. aq. NH4C1 was added, and the
mixture was
extracted three times with Et0Ac. The combined organic layers were washed with
water and
brine. The organic layer was then dried over MgSO4(s), filtered, and
concentrated in vacuo. The
mixture of four stereoisomers was purified by chiral preparative SFC (Step 1:
Lux-Cellulose-4
column, 25% Me0H/CO2, Step 2: AD-H, 35% Et0H/CO2) to afford Ex-114a (1st
eluting), Ex-
114b (2nd eluting), Ex-114c (31rd eluting), Ex-114d (4th eluting). Ex-114a: 'H
NMR (500 MHz,
Methanol-d4) 6 7.31 (dd, J= 5.8, 2.9 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.80 (t, J
= 74.0 Hz, 1H),
4.48- 4.41 (m, 3H), 4.41 -4.34 (m, 1H), 4.20 -4.12 (m, 2H), 3.02 (dd, J= 15.8,
5.4 Hz, 1H),
2.83 (dd, J = 15.8, 10.4 Hz, 1H), 2.72 (tdd, J = 11.4, 5.4, 2.5 Hz, 1H), 2.61 -
2.53 (m, 2H), 2.23
-2.16 (m, 2H), 2.16 - 2.04 (m, 2H), 1.97- 1.82 (m, 2H), 1.79- 1.72 (m, 4H),
1.72- 1.62 (m,
1H).
By using procedures similar to those described in Example 114 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
LCMS DGAT2
Example Structure Name
1M+11 IC50 (nM)
(6R)-3-(5-(difluoromethoxy)-2-
, * rF
fluoropheny1)-1-(2-
114a 'el\P 528
44.5
01- olf &OH hydroxycyclopenty1)-N-(3-
A
methyl-1,1-dioxidothietan-3-y1)-
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4,5,6,7-tetrahydro-1H-indazole-6-
carboxamide (1st eluting with Step
1: Lux Cellulose-4 column, 25%
Me0H/CO2; Step 2: AD-H
column, 35% Et0H/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-(2-
hydroxycyclopenty1)-N-(3 -
F (kr methy1-1,1-dioxidothietan-3-y1)-
114b c?1,01N; 4,5,6,7-tetrahydro-1H-indazole-6- 528
129.0
01 0 OH
carboxamide (211d eluting with
Step 1: Lux Cellulose-4 column,
25% Me0H/CO2; Step 2: AD-H
column, 35% Et0H/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-(2-
hydroxycyclopentyl)-N-(3 -
F Or methy1-1,1-dioxidothietan-3-y1)-
114c H op, \µ1,1 4,5,6,7-tetrahydro-1H-indazole-6- 528
99.9
carboxamide (3rd eluting with
Step 1: Lux Cellulose-4 column,
25% Me0H/CO2; Step 2: AD-H
column, 35% Et0H/CO2)
(6R)-3-(5-(difluoromethoxy)-2-
11uoropheny1)-1-(2-
hy-droxycyclopenty1)-N-(3 -
F 4i# C\r-F methyl-1,1-di oxi dothi etan-3 -y1)-
114d
rYd/r el OH 4,5,6,7-tetrahydro-1H-indazole-6- 528
105
1 V carboxamide (4th eluting with
Step 1: Lux Cellulose-4 column,
25% Me0H/CO2; Step 2: AD-H
column, 35% Et0H/CO2)
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EXAMPLE 115
(R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-N-(3-methy1-1,1-dioxidothietan-3-
y1)-1-
(methylsulfony1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
F 41* )--F FbF
E STEP A
H 0.11µN
riA 110 N
0 01µ
0 0
EX-115
STEP A: (R)-3-(5-(difluoromethoxy)-2-fluoropheny1)-N-(3-methy1-1,1-
dioxidothietan-3-y1)-1-
(methylsulfony1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
At 0 C, NaH (21.7 mg, 0.54 mmol) was added to a stirred solution of (R)-3-(5-
(difluoromethoxy)-2-fluoropheny1)-N-(3-methy1-1,1-dioxidothietan-3-y1)-4,5,6,7-
tetrahydro-1H-
indazole-6-carboxamide (60.0 mg, 0.14 mmol) and DMF (0.5 mL). The reaction
mixture was
stirred for 5 min at 0 C. Methanesulfonyl chloride (62.0 mg, 0.54 mmol) was
added and the
reaction mixture was stirred at rt for 30 minutes. Water was added and the
aqueous layer was
extracted three times with Et0Ac. The combined organic layers were washed with
water and
brine. The organic layer was then dried over MgSO4(s), filtered, and
concentrated in vacuo. The
crude product was purified by flash silica gel column chromatography (0-70%
Et0Ac/hexanes)
to afford the title compound. LC/MS = 522 [M-F11. 1H NMR (500 MHz, Chloroform-
d) 6 7.39
(dd, J = 5.7, 2.9 Hz, 1H), 7.22- 7.12 (m, 2H), 6.51 (t, J= 73.4 Hz, 1H), 5.93
(s, 1H), 4.50 - 4.37
(m, 2H), 4.16 - 4.08 (m, 2H), 3.38 (s, 3H), 3.29 (dd, J = 18.3, 5.8 Hz, 1H),
3.16 (dd, J = 17.8,
9.4 Hz, IH), 2.67 - 2.55 (m, 3H), 2.13 - 2.03 (m, IH), 1.89- 1.84 (m, IH),
1.82 (s, 3H).
DGAT2 IC50 (nm) = 107.5.
By using procedures similar to those described in Example 115 with appropriate
reagents, the
following compound was synthesized. This compound was characterized by LC/MS.
Example Structure Name LCMS DGAT2
[M+11 IC50 (nM)
116 F 0F (R)-1-(cyclopropylsulfony1)-3- 548
68.1
H =i 'NJ. (5-(difluoromethoxy)-2-
cSNI
0 fluoropheny1)-N-(3-methy1-1,1-
dioxidothietan-3-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-
carboxamide
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EXAMPLE 117
3-(3-(difluoromethoxy)pheny1)-4,4-difluoro-N-(3-methyl-1,1-
dioxidotetrahydrothiophen-3-y1)-1-
(tetrahydro-2H-pyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxamide
0
ur C).--.F
0 0
....,0 0 =z). ,F.,... ....0 , N.HHTs =3..E....1
101 'N STEP C ,.0 10 1 µN STEP D
-3m.- N.
0 0 ,.0 0=if
0 0
gi
)--F * )--F ab. )_..F F F
F F F F µ4"...
It F
, µ11
s s
..... 0 1110 1 Ft ...O S=17... ....0 el ris, s-,,,,... ..
Ho IP I N.%,N .. S=1,G... 0=C , .. a
,
b 0
b 0 b Ex-117 0
0 0 0
STEP A: Methy1-3-oxo-5-(2-tosylhydrazono)cyclohexane-1-carboxylate
To a stirred solution of methyl 3,5-dioxocyclohexane-l-carboxylate (3.3 g,
19.2 mmol), 4-
methylbenzenesulfonohydrazide (3.6 g, 19.2 mmol), and Me0H (38 mL) was added 5
drops of
sulfuric acid. The reaction mixture was stirred at rt for 16 h. The reaction
mixture was filtered
and precipitate collected. The crude product was used without purification.
LC/MS = 339 [M+1].
STEP B: Methyl 3-(3-(difluoromethoxy)pheny1)-4-oxo-4,5,6,7-tetrahydro-1H-
indazole-6-
carboxylate
To a stirred solution of methyl-3-oxo-5-(2-tosylhydrazono)cyclohexane-1-
carboxylate (1.5 g, 4.3
mmol), 3-(difluoromethoxy)benzaldehyde (0.8 g, 4.8 mmol), piperidine (0.47 mL,
4.78 mmol),
and DMSO (11 mL) was added acetic acid (0.03 mL, 0.43 mmol). The reaction
mixture was
stirred at 100 C for 10 min. The reaction mixture was cooled to rt and water
was added. The
aqueous layer was extracted three times with Et0Ac. The combined organic
layers were washed
with water and brine. The organic layer was then dried over MgSO4(s),
filtered, and
concentrated in vacuo. The crude product was purified by flash silica gel
column
chromatography (50% Et0Ac in hexanes) to afford the title compound. LC/MS =
337 [M+1].
STEP C: Methyl 3-(3-(difluoromethoxy)pheny1)-4-oxo-1-(tetrahydro-2H-pyran-4-
y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxylate
To a stirred solution of methyl 3-(3-(difluoromethoxy)pheny1)-4-oxo-4,5,6,7-
tetrahydro-1H-
indazole-6-carboxylate (600 mg, 1.78 mmol), tetrahydro-2H-pyran-4-y1 4-
methylbenzenesulfonate (915 mg, 3.57 mmol), and DMF (8.9 mL) was added Cs2CO3
(2.32 g,
7.14 mmol). The reaction mixture was stirred at 100 C for 1 h. After cooling
to rt, water was
added. The aqueous layer was extracted three times with Et0Ac. The combined
organic layers
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were washed with water and brine. The organic layer was then dried over
MgSO4(s), filtered,
and concentrated in vacuo. The crude product was purified by flash silica gel
column
chromatography (50% Et0Ac in hexanes) to afford the title compound. LC/MS =
421 IM+1].
STEP D: Methyl 3-(3-(difluoromethoxy)pheny1)-1-(tetrahydro-2H-pyran-4-y1)-
1,5,6,7-
tetrahydrospiro[indazole-4,2'41,31dithiolane1-6-carboxylate
To a stirred solution of methyl 3-(3-(difluoromethoxy)pheny1)-4-oxo-1-
(tetrahydro-2H-pyran-4-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (350 mg, 0.83 mmol), ethane-
1,2-dithiol (0.21
mL, 2.49 mmol), and DCM (4.2 mL) was added boron trifluoride acetic acid
complex (0.35 mL,
2.49 mmol). The reaction mixture was stirred at rt for 1 h and sat. aq. NaHCO3
was added. The
aqueous layer was extracted three times with DCM. The combined organic layers
were washed
with water and brine. The organic layer was then dried over MgSO4(s),
filtered, and
concentrated in vacuo. The crude product was purified by flash silica gel
column
chromatography (40% Et0Ac in hexanes) to afford the title compound. LC/MS =
497 IM+11.
STEP E: Methyl 3-(3-(difluoromethoxy)pheny1)-4,4-difluoro-1-(tetrahydro-2H-
pyran-4-y1)-
4,5,6,7-tetrahydro-1H-indazole-6-carboxylate
To a stirred solution of methyl 3-(3-(difluoromethoxy)pheny1)-1-(tetrahydro-2H-
pyran-4-y1)-
1,5,6,7-tetrahydrospiro[indazole-4,2'41,31dithiolane]-6-carboxylate (180 mg,
0.36 mmol), NIS
(245 mg, 1.08 mmol), and DCM (3.6 mL) at -78 C was slowly added pyridine-HF
(108 mg,
1.08 mmol). The reaction mixture was stin-ed at -78 'V for 1 h then warmed to
0 C and sat aq.
NaHCO3 was added. The aqueous layer was extracted three times with DCM. The
combined
organic layers were washed with 1 M aq. NaOH and brine. The organic layer was
then dried over
MgSO4(s), filtered, and concentrated in vacuo. The crude product was purified
by flash silica gel
column chromatography (50% Et0Ac in hexanes) to the title compound. LC/MS =
443 IM+11.
STEP F: 3-(3-(difluoromethoxy)pheny1)-4,4-difluoro-1-(tetrahydro-2H-pyran-4-
y1)-4,5,6,7-
tetrahydro-1H-indazole-6-carboxylic acid
To a stirred solution of methyl 3-(3-(difluoromethoxy)pheny1)-4,4-difluoro-1-
(tetrahydro-2H-
pyran-4-y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylate (67 mg, 0.15 mmol),
LiOH (14.5 mg,
0.60 mmol), THF (0.3 mL), and Me0H (0.1 mL) was added water (0.3 mL). The
reaction
mixture was stirred at rt for 5 min and then acidified with concentrated HCl
to pH 1. The
reaction mixture was then extracted with Et0Ac three times. The combined
organic layers with
washed with brine, dried with MgSO4(s), filtered, and concentrated in vacuo.
The crude product
was used without purification. LC/MS = 429 [M+11.
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STEP G: 3-(3-(difluoromethoxy)pheny1)-4,4-difluoro-N-(3-methy1-1,1-
dioxidotetrahydrothiophen-3-y1)-1-(tetrahydro-2H-pyran-4-y1)-4,5,6,7-
tetrahydro-1H-indazole-6-
carboxamide
To a stirred solution of 3-(3-(difluoromethoxy)pheny1)-4,4-difluoro-1-
(tetrahydro-2H-pyran-4-
y1)-4,5,6,7-tetrahydro-1H-indazole-6-carboxylic acid (55.6 mg, 0.13 mmol) in
DMF (0.6 mL)
was added DIPEA (0.11 mL, 0.65 mmol), HATU (59.2 mg, 0.16 mmol), and 3-amino-3-

methyltetrahydrothiophene 1,1-dioxide (23.2 mg, 0.16 mmol). The reaction
mixture was stirred
at rt for 5 min. The mixture was filtered and purified by mass triggered
reverse phase HPLC
(ACN/water with 0.1% FA modifier) to afford the title compound (Ex-117). LC/MS
= 560
[M+1]. DGAT2 IC50 (nm) = 498.9. The mixture of two stereoisomers was purified
by chiral
preparative SFC (IC column, 40% Et0H (0.1% DEA)/CO2) to afford Ex-117a (faster
eluting)
and Ex-117b (slower eluting). Ex-117b 1-1-1NMR (600 MHz, Chloroform-d) 6 7.85
(d, J= 9.5
Hz, 1H), 7.37 (t, ./= 7.9 Hz, 1H), 7.12 (d, ./= 7.9 Hz, 1H), 6.99 (d,.1 = 12.0
Hz, 1H), 6.58 (t, ./=
73.9 Hz, 1H), 4.38 -4.23 (m, 1H), 4.10 (d, J = 10.2 Hz, 2H), 3.84 (dd, J=
58.6, 13.8 Hz, 1H),
3.50 (p, ./= 12.7, 12.0 Hz, 2H), 3.34 (dq, ./ = 59.8, 11.5, 11.1 Hz, 1H), 3.21
(td, ./= 15.5, 10.3
Hz, 2H), 3.15 - 3.02 (m, 2H), 3.02 - 2.97 (m, 1H), 2.71 (dq, J= 34.5, 15.5,
15.0 Hz, 3H), 2.47 -
2.24 (m, 2H), 2.14 (p, J= 12.2 Hz, 1H), 1.87 (t, J= 14.0 Hz, 2H), 1.58 (d, J =
4.9 Hz, 3H).
LC/MS = 560 [M+1].
By using procedures similar to those described in Example 117 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
DGAT2
LCMS
Example Structure Name
IC50
[M+11
(nM)
(R)-3-(3-
(difluoromethoxy)pheny1)-4,4-
difluoro-N4S)-3-methyl-1,1 -
F F * OF dioxidotetrahydrothiophen-3-y1)-1-
117a
r_c=-! e' µ11 (tetrahydro-2H-pyran-4-y1)- 560
>10000
0 t)4,5,6,7-tetrahydro-1H-indazole-6-
0
carboxamide
(faster eluting with IC column,
40% Et0H (0.1% DEA)/CO2)
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0-343-
(difluoromethoxy)pheny1)-4,4-
difluoro-N-(0-3-methyl-1,1 -
F F * Or dioxidotetrahydrothiophen-3-y1)-1-
117b I (tetrahydro-2H-pyran-4-y1)- 560
177.6
03,0 8
4,5,6,7-tetrahydro-1H-indazole-6-
0
carhoxamide (slower eluting with
IC column, 40% Et0H (0.1%
DEA)/CO2)
EXAMPLE 118
3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-(3-methy1-1,1-
dioxidotetrahydrothiophen-3-y1)-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-6-
carboxamide
0
icsiNSTEP A meoyk Lc'?STEP B meolrUs> STEP
'SEM 'SEM o EM
0 0 0
I Nµ,1\I
Me0yr,....X> STEP ....011.X...X> STEP E
0 'SEM 0
STEP
F
0 STEP H 0
o F
STEPS
N -D.- 3 µ1,I
H1\1,
HO I Nr
05C 0 " o5C o
o'
Ex-118
Step A: methyl 2-(((142-(trimethylsilypethoxy)methyl)-1H-pyrazol-4-
ypoxy)methypacrylate
To a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-ol (3.0 g,
14.0 mmol) and
K2CO3 (5.8 g, 42.0 mmol) in DMF (17.5 ml) was added methyl 2-
(bromomethyl)acrylate (2.5
ml, 21.0 mmol). The reaction was stirred at rt for 1 h. Water was added to
quench the reaction,
followed by Et0Ac. The layers were separated, and the aqueous layer was
extracted three times
with Et0Ac. The combined organic layers were dried with MgSO4(s), filtered,
and concentrated
in vacuo. The residue was purified by flash silica gel column chromatography
(10% Et0Ac in
hexanes) to afford the title compound. LC/MS = 313 [M + 11.
STEP B: 142-(tri methyl si lypethoxy)methyl)-1,5-di hy dropyrano [3,2-c]
pyrazol e-6-carboxyl ate
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At rt, Pd(OAc)2 (0.29 g, 1.3 mmol), KOAc (1.89 g, 19.2 mmol), and acetylvaline
(0.41 g, 2.6
mmol) were added to a round bottom flask. Dioxane (14 ml) was added, followed
by a solution
of methyl 2-(((14(2-(trimethylsilypethoxy)methyl)-1H-pyrazol-4-
yl)oxy)methypacrylate (2.0 g,
6.4 mmol) in DMA (28 m1). A reflux condenser was placed over the flask open to
air. The
reaction was heated to 100 C and the reaction was stirred for 24 h. The
reaction was cooled to rt
and concentrated in vacuo. Brine and Et0Ac were added, the layers were
separated, and the
aqueous layer was extracted three times with Et0Ac. The organic layers were
dried with Na2SO4
(s), filtered, and concentrated. The residue was purified by flash silica gel
column
chromatography (0-50% Et0Ac in Hexanes) to afford the title compound. LC/MS =
311 [M +
1].
Step C: methyl 14(2-(trimethylsilyl)ethoxy)methyl)-1,5,6,7-
tetrahydropyrano[3,2-clpyrazole-6-
carboxylate
To a stirred solution of methyl 1-42-(trimethylsilypethoxy)methyl)-1,5-
dihydropyrano[3,2-
c[pyrazole-6-carboxylate (100 mg, 0.32 mmol) and Me0H (1.6 mL) was added 10%
Pd/C (34.3
mg, 0.32 mmol Pd). The mixture was sparged with N2 for 10 min, then a balloon
of H2 was
placed over the reaction mixture, the reaction mixture was sparged with Hz,
and the reaction
mixture was heated to 30 'V and stirred for 2 days. The mixture was then
filtered over Celite ,
which was washed with methanol, and the filtrate was concentrated under in
vacuo. The crude
residue was purified by flash silica gel column chromatography (0-50% Et Ac in
hexanes) to
afford the title compound. LC/MS = 313 M + 11.
Step D: methyl 1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-6-carboxylate
To a stirred solution of methyl 14(2-(trimethylsilypethoxy)methyl)-1,5,6,7-
tetrahydropyrano[3,2-clpyrazole-6-carboxylate (58 mg, 0.19 mmol) in DCM (743
IA) at 0 C
was added TFA (143 tl, 1.86 mmol). The mixture was allowed to warm to rt and
was stirred for
2 h. After that time, TFA (143 1.11, 1.86 mmol) was added at rt, and the
reaction was continued.
After an additional 3 h, TFA (71.5 1, 0.93 mmol) was added at rt, and the
reaction was
continued. After an additional 2 h, the reaction was concentrated in vacuo.
The crude residue was
purified by flash silica gel column chromatography (0-10% Me0H in DCM) to
afford the title
compound. LC/MS = 183 WI + 11.
Step E: methyl 3-iodo-1,5,6,7-tetrahydropyrano[3,2-clpyrazole-6-carboxylate
To a stirred solution of methyl 1,5,6,7-tetrahydropyrano[3,2-clpyrazo1e-6-
carboxy1ate (28 mg,
0.15 mmol) in DMF (615 pi) was added NIS (51.9 mg, 0.23 mmol), and the
reaction was heated
to 80 'V for 1 h. The reaction was then cooled to rt and quenched with sat.
aq. NaHCO3. Et0Ac
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was added, the layers were separated, and the aqueous layer was extracted
three times with
Et0Ac. The combined organic layers were dried with MgSO4(s), filtered, and
concentrated in
vacuo. The crude residue was purified via flash silica gel column
chromatography (0-10%
Me0H in DCM) to afford the title compound. LC/MS = 309 [1\4 + 1].
Step F: 3-(3-(difluoromethoxy)pheny1)-1,5,6,7-tetrahydropyrano[3,2-clpyrazole-
6-carboxylic
acid
A mixture of methyl 3-iodo-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-6-
carboxylate (24 mg, 0.08
mmol), (3-(difluoromethoxy)phenyl)boronic acid (17.6 mg, 0.09 mmol),
Pd(dppf)C12 (5.7 mg,
7.8 umol), and Na2CO3 (16.5 mg, 0.16 mmol) was put under N2, and dioxane (195
up and water
(195 ul) were added. The mixture was heated to 100 C for 1 h. The reaction
was cooled to rt,
water was added, and the pH was adjusted to 2 with 1 N HC1. The aqueous layer
was extracted
with Et0Ac three times, and the combined organic layers were dried with
MgSO4(s), filtered,
and concentrated in vacuo. The crude product was used without purification.
LC/MS = 311 [M +
1].
Step C: 3-(3-(difluoromethoxy)pheny1)-N-(3-methy1-1,1-
dioxidotetrahydrothiophen-3-y1)-
1,5,6,7-tetrahydropyrano3,2-clpyrazole-6-carboxamide
To a stirred solution of 3-(3-(difluoromethoxy)pheny1)-1,5,6,7-
tetrahydropyrano3,2-c]pyrazole-
6-carboxylic acid (24 mg, 0.08 mmol), HATU (32.4 mg, 0.09 mmol), and 3-amino-3-

methyltetrahydrothiophene 1,1-dioxide (12.7 mg, 0.09 mmol) in DMF (387 pl) was
added
DIPEA (40.5 0.23
mmol). The reaction was stirred for 1 h at rt, then concentrated in vacuo.
The crude residue was first purified by flash silica gel column chromatography
(0-100% Et0Ac
in Hexanes), then again by flash silica gel column chromatography (0-10% Me0H
in DCM) to
afford the title compound. LC/MS = 442 [M+ 11.
Step H: 3-(3-(difluoromethoxy)pheny1)-1-(5-fluoropyridin-2-y1)-N-(3-methy1-1,1-
dioxidotetra-
hy drothiophen-3 -y1)-1,5,6,7-tetrahy dropy rano 113,2-clpyrazole-6-carb
oxamide
To a stirred solution of 3-(3-(difluoromethoxy)pheny1)-N-(3-methy1-1,1-
dioxidotetrahydro-
thiophen-3-y1)-1,5,6,7-tetrahydropyrano113,2-clpyrazole-6-carboxamide (6 mg,
0.01 mmol), 2-
bromo-5-fluoropyridine (3.6 mg, 0.02 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-
1,2-diamine
(9.7 mg, (107 mmol), Cal (1.3 mg, 6.8 umol), and dioxane (400 ul) was added
K3PO4 (8.7 mg,
0.04 mmol). The reaction was heated to 100 C for 1.5 h. The mixture was then
was cooled to rt,
diluted with acetone, and purified directly by flash silica gel column
chromatography (0-100%
Et0Ac in hexanes) to afford the title compound Ex-118. LC/MS = 537 [M + 11.
DGAT2 IC50
(nm) =0.44.
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By using procedures similar to those described in Example 118 with appropriate
reagents, the
following compound was synthesized. These compounds were characterized by
LC/MS.
LCMS DGAT2
Example Structure Name
[M+11 IC50 (nM)
3-(3-(difluoromethoxy)pheny1)-1-(5-
4kO fluoropyridin-2-y1)-N-(3-methy1-1,1-
0
µN dioxidothietan-3-y1)-1,5,6,7-
119 00< 523
0.33
0 \ tetrahydropyrano[3,2-cipyrazole-6-
F carboxamide (mixture of
enantiomers)
EXAMPLE 120
3-(3-(difluoromethoxy)pheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-3-y1)-
1,5,6,7-
tetrahydropyrano[3,2-clpyrazole-6-carboxamide
HO r0 Cr
meo r%1 STEP A
N mealikrµsrN STEPS, meoIrci I e STEP Ci meo I NN,N
1Cr 'SEM 0 SEM 0 'SEM 0
STEP D I N1,1 STEP E 0 STEP F 0 STEP G
.
Me0 I NN I NN
Me0 HO
1,1µ
0 0
N\jµi S1=,
S5 0
0."g 0.11
0
EX-120
Step A: Methyl 2-((4-hydroxy-1-((2-(trimethylsilypethoxy)methyl)-1H-pyrazol-5-
yOmethypacrylate
A solution of methyl 2-(((142-(trimethylsilypethoxy)methyl)-1H-pyrazol-4-
yl)oxy)methyl)acrylate (9.6 g, 30.7 mmol) and DMA (288 mL) was stirred at 120
C for 16 h.
After cooling to rt, water was added and the aqueous layer was extracted three
times with
Et0Ac. The combined organic layers were washed with water and brine. The
organic layer was
then dried over Na2SO4(s), filtered, and concentrated in vacuo. The crude
product was used
without purification. LC/MS = 313 [M + 1].
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Step B: Methyl 1-02-(trimethylsilypethoxy)methyl)-1,5,6,7-tetrahydropyrano[3,2-
c[pyrazole-6-
carboxylate
To a stirring solution of methyl 2-((4-hydroxy-14(2-
(trimethylsilypethoxy)methyl)-1H-pyrazol-
5-yOmethypacrylate (5 g, 16 mmol) and toluene (100 mL) was added Cs2CO3 (5.21
g, 16 mmol).
The reaction mixture was stirred at 55 C for 16 h. After cooling to rt, the
reaction mixture was
filtered and concentrated. The crude product was purified by flash silica gel
column
chromatography (15% Et0Ac in hexanes) to afford the title compound. LC/MS =
313 [M+1[.
Step C: Methyl 1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-6-carboxylate
To a stirring solution of methyl 142-(trimethylsilypethoxy)methyl)-1,5,6,7-
tetrahydropyrano113,2-clpyrazole-6-carboxylate (2.2 g, 7.04 mmol) and DCM (14
mL) was added
TFA (10.9 mL, 141 mmol). The reaction mixture was stirred at rt for 16 h. The
reaction mixture
was washed with sat. aq. NaHCO3 and brine. The organic layer was then dried
over MgSO4(s),
filtered, and concentrated in vacuo. The crude product was used without
purification. LC/MS =
183 [M + 11.
Step D: Methyl 3-iodo-1,5,6,7-tetrahydropyrano[3,2-c[pyrazole-6-carboxylate
To a stirring solution of methyl 1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-6-
carboxylate (0.97 g,
5.3 mmol) and DMF (13 mL) was added NIS (1.44 g, 6.4 mmol). The reaction
mixture was
stirred at 80 C for 1.5 h. After cooling to rt, sat. aq. NaHCO3 was added and
the aqueous layer
was extracted three times with Et0Ac. The combined organic layers were washed
with water and
brine, dried over MgSO4(s), filtered, and concentrated in vacuo. The crude
product was purified
by flash silica gel column chromatography (100% Et0Ac) to afford the title
compound. LC/MS
= 309 [M+11.
Step E: Methyl 3-(3-(difluoromethoxy)pheny1)-1,5,6,7-tetrahydropyrano[3,2-
clpyrazole-6-
carboxylate
To a stirred solution of methyl 3-iodo-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-
6-carboxylate
(500 mg, 1.62 mmol), (3-(difluoromethoxy)phenyl)boronic acid (336 mg, 1.78
mmol),
Pd(dppf)C12 (238 mg, 0.33 mmol), Na2CO3 (344 mg, 3.25 mmol), and dioxane (8.1
mL) was
added water (8.1 mL). The reaction mixture was sparged with N2 for 5 mm at rt
then heated to
100 'V for 5 mm. After cooling to rt, water was added and the mixture was
extracted three times
with Et0Ac. The combined organic layers were washed with water and brine,
dried over MgSO4
(s), filtered, and concentrated in vacuo. The crude product was purified by
flash silica gel
column chromatography (50% Et0Ac) to afford the title compound. LC/MS = 325
[M+1].
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STEP F: 3-(3-(difluoromethoxy)pheny1)-1,5,6,7-tetrahydropyrano[3,2-c]pyrazole-
6-carboxylic
acid
To a mixture of methyl 3-(3-(difluoromethoxy)pheny1)-1,5,6,7-
tetrahydropyrano[3,2-c[pyrazole-
6-carboxylate (197 mg, 0.6 mmol), LiOH (58 mg, 2.4 mmol), THF (1.0 mL), Me0H
(1.0 mL),
and water (1.0 mL). The mixture was stirred at rt for 10 minutes, then
acidified with
concentrated HC1 to pH 1. The mixture was then extracted three times with
Et0Ac. The
combined organic layers were washed with water and brine, dried over MgSO4(s),
filtered, and
the volatiles evaporated to afford the title compound. The crude product was
used without
purification. LC/MS = 311 [M-P11.
STEP G: 3-(3-(difluoromethoxy)pheny1)-N-(3-meihyl-1,1-dioxidothietan-3-y1)-
1,5,6,7-
tetrahydropyrano[3,2-clpyrazole-6-carboxamide
To a mixture of 3-(3-(difluoromethoxy)pheny1)-1,5,6,7-tetrahydropyrano[3,2-
c[pyrazole-6-
carboxylic acid (193 mg, 0.62 mmol) in DMF (2.1 mL) was added HATU (284 g,
0.75 mmol),
DIPEA (543 viL, 3.1 mmol), and then 3-amino-3-methylthietane 1,1-dioxide
hydrochloride (128
mg, 0.75 mmol). The mixture was stirred at rt for 5 minutes. Then water was
added and the
aqueous layer was extracted three times with Et0Ac. The combined organic
layers were washed
with water and brine. The organic layer was then dried over MgSO4(s),
filtered, and
concentrated in vacuo. The crude product was purified by flash silica gel
column
chromatography (100% Et0Ac) to afford the title compound. LC/MS = 428 [M+11.
STEP H: 3-(3-(difluoromethoxy)pheny1)-1-isopropyl-N-(3-methyl-1,1-
dioxidothietan-3-y1)-
1,5,6,7-tetrahydropyrano[3,2-clpyrazole-6-carboxamide
To a mixture of 3-(3-(difluoromethoxy)pheny1)-N-(3-methyl-1,1-dioxidothietan-3-
y1)-1,5,6,7-
tetrahydropyrano[3,2-clpyrazole-6-carboxamide (157 mg, 0.37 mmol), 2-
iodopropane (125 mg,
0.74 mmol), Cs2CO3 (479 mg, 1.47 mmol) was added DMF (1.2 m1). The mixture was
stirred at
100 C for 15 minutes. The reaction mixture was cooled to rt, filtered, and
purified by mass
triggered reverse phase HPLC (ACN/water with 0.1% FA modifier) to afford the
title compound
(Ex-120). LC/MS = 470 [M-F11. DGAT2 IC50 (nm) = 18.8. The mixture of two
stereoisomers
was purified by chiral preparative SFC (AD-H column, 35% Me0H/CO2) to afford
Ex-120a
(faster eluting) and Ex-120b (slower eluting). 1H NMR (500MHz, Me0D) 6 7.54
(t, J = 8.0 Hz,
1H), 7.28 (d, .J= 7.8 Hz, 1H), 7.16 - 7.23 (m, 2H), 6.72- 7.09(m. 1H), 4.55
(td, = 13.2 Hz, .12
= 6.6 Hz, 1H), 4.46 (d, J= 14.8 Hz, 2H), 4.36 (br d, J= 11.1 Hz, 1H), 4.13 -
4.20 (m, 2H), 3.98 -
4.05 (m, 1H), 3.95 - 3.05 (m, 3H), 1.76 (s, 3H), 1.43 (dd, J, = 15.8 Hz, J2=
6.6 Hz, 6H).
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By using procedures similar to those described in Example 120 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
LCMS DGAT2
Example Structure Name
[M+1] IC50 (nM)
(S)-3-(3-(difluoromethoxy)pheny1)-1_
isopropyl-N-(3-methy1-1,1-
. dioxidothietan-3-y1)-1,5,6,7-
120a'
8 tetrahydropyrano[3,2-c]pyrazole-6- 470 7.6
N
carboxamide (faster eluting with AD-
H column, 40% Me0H/CO2)
(R)-3-(3-(difluoromethoxy)pheny1)-1-
*
isopropyl-N-(3-methyl-1,1-
F dioxidothietan-3-y1)-1,5,6,7-
120b HI ,N 470
>10000
ci.N1
0-4 tetrahydropyrano[3,2-cipyrazole-6-
o carboxamide (slower eluting with
AD-H column, 40% Me0H/CO2)
3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-isopropyl-N-(3-
F
0F methy1-1,1-dioxidothietan-3-y1)-
121 INN 488
21.5
N
1,5,6,7-tetrahydropyrano[3,2-
o clpyrazole-6-carboxamide (mixture of
enantiomers)
3-(5-(difluoromethoxy)-2-
fluoropheny1)-1-isopropyl-N-((S)-3-
F * c\rF methyl-i,1-
122 I\,N dioxidotetrahydrothiophen-3-y1)-
502 5.8
OcTpl. 0 1,5,6,7-tetrahydropyrano[3,2-
clpyrazole-6-carboxamide (mixture of
diastereomers)
3-(5-(difluoromethoxy)-2-
F *
0 fluoropheny1)-1-i s opropyl-N-((R)-3-
123 H I 502
24.3
0-4 N
0 methyl-1,1-
dioxidotetrahydrothiophen-3-y1)-
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1,5,6,7-tetrahydropyrano[3,2-
clpyrazole-6-carboxamide (mixture of
diastereomers)
N-(3,3-difluoro-1-methylcyclobuty1)-
3-(3-(difluoromethoxy)pheny1)-1 -
Fµ F
isopropyl-1,5,6,7-
124 H
456 56.4
N
tetrahydropyrano[3,2-c]pyrazole-6-
FfL
carboxamide
(mixture of enantiomers)
(S)-3-(3-cyclopropylpheny1)-1-
isopropyl-N-(3-methyl-1,1-
125 H \ N dioxidothietan-3-y1)-1,5,6,7- 444
22.2
,s 0
tetrahydropyrano[3,2-c]pyrazole-6-
carboxamide
EXAMPLE 126
3-(3-(difluoromethoxy)pheny1)-1-isopropyl-N-(3-methy1-1,1-dioxidothietan-3-y1)-
1,4,6,7-
tetrahydropyrano[4,3-clpyrazole-6-carboxamide
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BocHN 0 0 0
0 0
/ 0
STEP A STEP B STEP C OMe STEP D
=.)N _]....
qMe
NI I
_].... _].....
N PMB¨N, .... NfN k
111 PMB ril
PMB FMB
HO 0
STEP E ...._
OMe

oF10
.......ist), OH
STEP H._ STEP 0 0 . STEP H
0 0 oN
N
.=-= , = N = N NI,
ril PMB PM PME! 0
PMB
I I
0 , µ
STEP I CD 1 =N STEP J ._ 0 0 0 1
. NI v . STEP K
Kr.==== NI ...
H '.. õ, N' .===="" NI
I li* )---F ii*, 0)......F * 0).....F
N_< S1).1 ...._ F 0 F STEP M
HO F
--- I
N' N
0
F F
STEP N STEP 0
),... L Fri 0 1..1 ON
N. .......r N . N
Cs.-5 0 )..-.". Is=-=1 0 )--
oil oil
0 0
EX-126
Step A: 1-(4-methoxybenzy1)-1H-pyrazole-5-carbaldehyde
To a solution of 1H-pyrazole-5-carbaldehyde (8.9 g, 93 mmol) in acetonitrile
(180 mL) was
added K2CO3 (38.4 g, 278 mmol) and 1-(chloromethyl)-4-methoxybenzene (21.76 g,
139 mmol)
at 25 C. The mixture was stirred at 25 C for 16 h, then poured into sat. NI-
14C1, and extracted
with DCM (x 3). The combined organic layers were washed with brine, dried over
Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified by
column
chromatography on silica (0-100% Et0Ac/hexanes) to afford the title compound.
LC/MS = 217
[M+1].
Step B: (E)-methyl 2-((tert-butoxycarbonypamino)-3-(1-(4-methoxybenzy1)-1H-
pyrazol-3-
y1)acrylate
To a solution of methyl 2-((tert-butoxycarbonyDamino)-2-
(dimethoxyphosphoryl)acetate (9.62 g,
32.4 mmol) at -78 C was added 1,1,3,3-tetramethylguanidine (4.85 g, 42.1
mmol). The mixture
was stirred for 15 mm, then 1-(4-methoxybenzy1)-1H-pyrazo1e-3-carba1dehyde (7
g, 32.4 mmol)
was added. The reaction was stirred for 1 h at -78 C and 1.5 h at 25 C. The
mixture was poured
into sat. NH4C1, then extracted with DCM (x 3). The combined organic layers
were washed with
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brine, dried over Na2SO4, then filtered and concentrated under reduced
pressure. The residue was
purified by column chromatography on silica (0-100% Et0Ac/hexanes) to afford
the title
compound. LC/MS = 388 1M+1].
Step C: methyl 3-(1-(4-methoxybenzy1)-1H-pyrazol-3-y1)-2-oxopropanoate
To a solution of (E)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1-(4-
methoxybenzy1)-1H-
pyrazol-3-yl)acrylate (11.9g. 30.7 mmol) in CH2C12 (100 mL) was added TFA (60
mL, 779
mmol) at 0 C. The mixture was stirred at 25 C for 16 h. LCMS showed the
reaction was
complete. The mixture was cooled, and the solvent was evaporated under reduced
pressure. A
saturated solution of NaHCO3 was added until the pH reached to 8, the aqueous
phase was
extracted with DCM (x 3), filtered and the solvent was evaporated under
reduced pressure to
afford the crude title compound, which was used into next step directly. LC/MS
= 389 1M+1].
Step D: methyl 2-hydroxy-3-(1-(4-methoxybenzy1)-1H-pyrazol-3-y1)propanoate
To a solution of methyl 3-(1-(4-methoxybenz.y1)-1H-pyrazol-3-y1)-2-
oxopropanoate (9.8 g, 34.0
mmol) in THF (100 mL) was added NaBH4 (1.929 g, 51.0 mmol) at 0 C under N2
atmosphere.
The mixture was stirred at 25 C for 15 min, then poured into sat. NH4Cland
extracted with
DCM (x 3) The combined organic layers were washed with brine, dried over
Na2SO4, then
filtered and concentrated under reduced pressure. The residue was purified by
column
chromatography on silica (0-100% Et0Ac/hexanes) to afford the title compound.
LC/MS = 291
1M+11_
Step E: methyl 2-hydroxy-3-(4-iodo-1-(4-methoxybenzy1)-1H-pyrazol-3-
y1)propanoate
To a solution of methyl 2-hydroxy-3-(1-(4-methoxybenzy1)-1H-pyrazol-3-
y0propanoate (1 g,
3.44 mmol) in DMF (10 mL) was added NIS (1.162 g, 5.17 mmol) at 25 'V under N2
atmosphere. The mixture was stirred at 25 C for 6 h, then poured into sat.
NH4C1, and extracted
with DCM (x 3). The combined organic layers were washed with brine, dried over
Na2SO4, then
filtered and concentrated under reduced pressure. The residue was purified by
column
chromatography on silica (0-100% Et0Ac/hexanes) to afford the title compound.
LC/MS = 417
1M+11.
Step F: methyl 2-hydroxy-3-(1-(4-methoxybenzy1)-4-viny1-1H-pyrazol-3-
y1)propanoate
To a solution of methyl 2-hydroxy-3-(4-iodo-1-(4-methoxybenzy1)-111-pyrazol-3-
y1)propanoate
(1.4 g, 3.36 mmol) in dioxane (6 mL)/water (2 mL) was added potassium
vinyltrifluoroborate
(0.901 g, 6.73 mmol), K2CO3 (1.395 g, 10.09 mmol) and PdC12(dppf) (0.492 g,
0.673 mmol)
under N2 atmosphere. The mixture was stirred at 90 C for 4 h. The mixture was
poured into sat.
NH4C1, then extracted with DCM (x 3). The combined organic layers were washed
with brine,
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dried over Na2SO4, then filtered and concentrated under reduced pressure. The
residue was
purified by column chromatography on silica (0-100% Et0Ac/hexanes) to afford
the title
compound. LC/MS = 317 [M+1].
Step G: methyl 4-hydroxy-2-(4-methoxybenzy1)-2,4,6,7-tetrahydropyrano[4,3-
clpyrazole-6-
carboxylate or methyl 4-hydroxy-1-(4-methoxybenzy1)-1,4,6,7-
tetrahydropyrano[4,3-cipyrazole-
6-carboxylate
To a solution of methyl 2-hydroxy-3-(1-(4-methoxybenzy1)-4-viny1-1H-pyrazol-3-
y1)propanoate
(750 mg, 2.371 mmol) in dioxane (5 mL)/water (1 mL) was added 2,6-lutidine
(0.552 mL, 4.74
mmol), sodium periodate (1014 mg, 4.74 mmol) and osmium tetroxide (0.372 mL,
1.185 mmol)
under N2 atmosphere. The mixture was stirred at 50 C for 1 h. The mixture was
poured into sat.
NH4C1, then extracted with DCM (x 3). The combined organic layers were washed
with brine,
dried over Na2SO4, then filtered and concentrated under reduced pressure. The
residue was
purified by column chromatography on silica (0-100% Et0Ac/hexanes) to afford
the title
compound. LC/MS = 319 [M+1].
Step H: methyl 2-(4-methoxybenzy1)-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-6-
carboxylate
To a solution of methyl 4-hydroxy-2-(4-methoxybenzy1)-2,4,6,7-
tetrahydropyrano[4,3-
c[pyrazole-6-carboxylate (400 mg, 1.257 mmol) in TFA (2 mL, 26.0 mmol) was
added
triethylsilane (1.606 mL, 10.05 mmol) under N2 atmosphere. The mixture was
stirred at 25 C
for 1h. The mixture was evaporated under reduced pressure to give the crude
product The crude
product was purified by column chromatography on silica (0-100% Et0Ac/hexanes)
to afford
the title compound. LC/MS = 303 11M+11.
Step I: methyl 2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-6-carboxylate
A solution of methyl 2-(4-methoxybenzy1)-2,4,6,7-tetrahydropyrano[4,3-
c]pyrazole-6-
carboxylate (200 mg, 0.662 mmol) in TFA (0.051 mL, 0.662 mmol) was stirred at
120 C for 1
h. The mixture was filtered and the solvent was evaporated under reduced
pressure to give the
crude product, which was purified by mass triggered reverse phase HPLC
(ACN/water with
0.1% TFA modifier) to afford the title compound. LC/MS = 183 [M+1].
Step J: methyl 3-iodo-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-6-carboxylate
To a solution of methyl 2,4,6,7-tetrahydropyrano[4,3-clpyrazole-6-carboxylate
(95 mg, 0.521
mmol) in DMF (1 mL) was added NIS (176 mg, 0.782 mmol) under N2 atmosphere.
The mixture
was stirred at 60 C for 1 h, then evaporated under reduced pressure to give
the crude product.
The crude product was purified by mass triggered reverse phase HPLC (ACN/water
with 0.1%
TFA modifier) to afford the title compound. LC/MS = 309 [M+1].
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Step K: methyl 3-iodo-1-isopropy1-1,4,6,7-tetrahydropyrano[4,3-clpyrazole-6-
carboxylate and
methyl 3-iodo-2-isopropyl-2,4,6,7-tetrahydropyrano[4,3-clpyrazole-6-
carboxylate
To a solution of methyl 3-iodo-2,4,6,7-tetrahydropyrano[4,3-c]pyrazole-6-
carboxylate (65 mg,
0.211 mmol) in acetonitrile (4 mL) was added Cs2CO3 (206 mg, 0.633 mmol) and 2-
iodopropane
(179 mg, 1.055 mmol) The mixture was stirred at 50 C for 3 h, then filtered.
The solvent was
evaporated under reduced pressure to give the crude product, and the crude
product was purified
by mass triggered reverse phase HPLC (ACN/water with 0.1% TFA modifier) to
afford the title
compound. LC/MS = 351 11\4+1].
Step L: methyl 3-(3-(difluoromethoxy)pheny1)-1-isopropy1-1,4,6,7-
tetrahydropyrano[4,3-
c]pyrazole-6-carboxylate and methyl 3-(3-(difluoromethoxy)pheny1)-2-isopropy1-
2,4,6,7-
tetrahydropyrano[4,3-clpyrazole-6-carboxylate
To a solution of methyl 3-iodo-l-isopropy1-1,4,6,7-tetrahydropyrano[4,3-
c]pyrazole-6-
carboxylate (30 mg, 0.086 mmol) and methyl 3-iodo-2-isopropy1-2,4,6,7-
tetrahydropyrano[4,3-
c]pyrazole-6-carboxylate (30.0 mg, 0.086 mmol) in dioxane (3 mL)/water (0.5
mL) was added
Na2CO3 (27.2 mg, 0.257 mmol), 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-
tetramethyl-1,3,2-
dioxaborolane (50.9 mg, 0.188 mmol) and PdC12(dppf) (12.54 mg, 0.017 mmol)
under N2
atmosphere The mixture was stirred at 80 'V for 3 h, then filtered, and the
solvent was
evaporated under reduced pressure to give the crude product, which was
purified by mass
triggered reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford the
title
compound. LC/MS = 367 [M+1].
Step M: 3-(3-(difluoromethoxy)pheny1)-1-isopropy1-1,4,6,7-tetrahydropyrano[4,3-
clpyrazole-6-
carboxylic acid
To a solution of methyl 3-(3-(difluoromethoxy)pheny1)-1-isopropy1-1,4,6,7-
tetrahydropyrano[4,3-clpyrazole-6-carboxylate (23 mg, 0.063 mmol) in Me0H (1
mL)/water
(0.2 mL) was added LiOH=H20 (3.01 mg, 0.126 mmol) at room temperature. The
solution was
stirred at 25 C for 3 h. LCMS showed the reaction was complete. The mixture
was concentrated
under reduced pressure. The residue was dissolved in H20. HC1 (1N in water)
was added to the
mixture until pH = 4. Then the mixture was extracted with DCM (x 3). The
combined organic
layers were washed with brine, dried over Na2SO4, then filtered and
concentrated under reduced
pressure to afford the title compound. LC/MS = 353 [M+1].
Step N: 3-(3-(difluoromethoxy)pheny1)-1-isopropyl-N-(3-methy1-1,1-
dioxidothietan-3-y1)-
1,4,6,7-tetrahydropyrano[4,3-clpyrazole-6-carboxamide
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To a mixture of 3-(3-(difluoromethoxy)pheny1)-1-isopropy1-1,4,6,7-
tetrahydropyrano[4,3-
c]pyrazole-6-carboxylic acid (18 mg, 0.051 mmol) in DCM (3 mL) was added DIEA
(0.027 mL,
0.153 mmol), HATU (38.9 mg, 0.102 mmol) and 3-amino-3-methylthietane 1,1-
dioxide (8.29
mg, 0.061 mmol) at 25 C. The mixture was stirred at 25 C for 2 h, then
filtered, and the solvent
was evaporated under reduced pressure to give the crude product, which was
purified by mass
triggered reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford the
title
compound. LC/MS = 470 [M+1]. The mixture of the two stereoisomers was purified
by chiral
SFC (Phenomenex-Cellulose-2 column, 40%/60% ethanol/CO2) to afford isomer EX-
134a
(faster eluting). LC/MS = 470 [M+11. 1H NMR (500 MHz, Me0D) 6 7.24 - 7.36 (m,
3H), 6.99
(dd, J1 = 7.3 Hz, J2 = 1.8 Hz, 1H), 6.56 - 6.88 (m, 1H), 4.85 - 4.96 (m, 2H),
4.41 - 4.48 (m, 3H),
4.06 - 4.16 (m, 3H), 3.03 - 3.07 (m, 1H), 2.72 (dd, J1 = 15.8 Hz, J2 = 10.8
Hz, 1H), 1.65 - 1.70
(m, 3H), 1.42 (dd, J1 = 10.1 Hz, J2 = 6.7 Hz, 6H). DGAT2 IC5() (nM) >10000 nM,
Isomer EX-
134b (slower eluting). LC/MS = 470 M 11.1-
1H NMR (500 MHz, Me0D) 6 7.24 - 7.35 (m, 3H),
6.95 -7.02 (m, 1H), 6.53 -6.86 (m, 1H), 4.85 -4.98 (m, 2H), 4.40 - 4.49 (m,
3H), 4.06 - 4.16 (m,
3H), 3.04- 3.08 (m, 1H), 2.72 (dd, J1 = 15.8 Hz, J2 = 10.8 Hz, 1H), 1.68 (s,
3H), 1.43 (dd, J1 =
10.4 Hz, J2 = 6.7 Hz, 6H). DGAT2 IC5o (nM) = 7607 nM. The structure of final
compounds was
confirmed by 2D NMR.
By using procedures similar to those described in Example 126 with appropriate
reagents, the
following compounds were synthesized. These compounds were characterized by
LC/MS.
DGAT2
LCMS
Example Structure Name
ICso
[M+11
(nM)
(R)-3-(5-(difluoromethoxy)-2-
F 4#*).F
F fluoropheny1)-1-isopropyl-N-(3-
127 I N methyl-1,1-dioxidothietan-3-y1)-
488 343
ri,Nir
1,4,6,7-tetrahy dropy rano [4,3 -
c]pyrazole-6-carboxamide
* 4 (R)-3-(5-cyclopropy1-2-
fluoropheny1)-1-isopropyl-N-(3-
128 H0 \ N
methyl-1,1-dioxidothietan-3-y1)- 462
320
N
1,4,6,7-tetrahydropyrano[4,3-
o
c]pyrazole-6-carboxamide
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ASSAYS
Insect cell expression and membrane preparation
Sf-9 insect cells were maintained in Grace's insect cell culture medium with
10 % heated-
inactivated fetal bovine serum, 1 % Pluronic F-68 and 0.14 ug/m1Kanamycine
sulfate at 27 C
in a shaker incubator. After infection with untagged baculovirus expressing
human DGAT2
(hDGAT2) at multiplicity of infection (MOD 3 for 48 hours, cells were
harvested. Cell pellets
were suspended in buffer containing 10 mM Tris-HC1 pH 7.5, 1 mM EDTA, 250 mM
sucrose
and Complete Protease Inhibitor Cocktail (Sigma Aldrich), and sonicated on
ice. Cell debris
were removed by centrifugation at 2000 x g for 15 minutes. Membrane fractions
were isolated
by ultracentrifugation (100,000 x g), resuspended in the same buffer, and
frozen (- 80 C) for
later use. The protein concentration was determined with the PierceTM BCA
Protein Assay Kit
(Thermo Fisher Scientific). Expression of protein levels was analyzed by
immunoblotting with
rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L
Alexa Fluor
647 (Abcam, abl 50075) followed by detection using Typhoon FLA9000 (GE
Healthcare).
LC/MS/MS analysis method
LC/MS/MS analyses were performed using Thermal Fisher's LX4-TSQ Vantage
system. This
system consists of an Agilent binary high-performance liquid chromatography
(HPLC) pump
and a TSQ Vantage triple quadrupole MS/MS instrument. For each sample, 2 uL
samples from
the top organic layer of in-plate liquid-liquid extraction were injected onto
a Thermo Betabasic
C4 column (2.1 mm x 20 mm, 5 um particle size). The samples were then eluted
using the
following conditions; mobile phase: Isopropanol: acetonitrile/10mM ammonium
formate =
50/35/15 (v/v/v), flow rate: 0.8 mL/min, temperature: 25 C. Data was acquired
in positive mode
using a heated electrospray ionization (HEST) interface. The operational
parameters for the TSQ
Vantage MS/MS instrument were a spray voltage of 3000 V, capillary temperature
of 280 C,
vaporizer temperature 400 C, sheath gas 45 arbitrary unit, Aux gas 10
arbitrary units, S-lens 165
and collision gas 1.0mTorr. Standard reference material (SRM) chromatograms of
13C18-triolein
(Q1: 920.8>Q3:621.3) and internal standard '3C21-triolein (Q1: 923.8>Q3:617.3)
were collected
for 33 sec. The peak area was integrated by Xcalibur Quan software. The ratio
between the
13C18triolein generated in the reaction and spiked in internal standard 13C21-
triolein was used to
generate percentage inhibition and IC50 values. Compound percentage inhibition
was calculated
by the following formula: Inhibition %=1-{(compound response ¨ low
control)/(high control ¨
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low control)] x 100%. Potent compounds were titrated and ICso were calculated
by 4 parameter
sigmoidal curve fitting formula.
DGAT2 enzymatic activity assay
DGAT2 activity was determined by measuring the amount of enzymatic product 13C
is-triolein
(nC-1,2,3-Tri(cis-9-octadecenoyl)glycerol) using the membrane prep mentioned
above. The
assay was carried out in ABgene 384-well assay plates in a final volume of 25
pi at rt. The
assay mixture contained the following: assay buffer (100 mM Tris=Cl, pH 7.0,
20 m1\4 MgCl2,
5% ethanol), 251,1M of diolein, 5 p.1\4 of 13C oleoyl-CoA and 8 ng/ .1_, of
DGAT2 membrane.
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Representative Drawing